stem cell research case studies

Clinical Trials

Stem cell therapy.

Displaying 74 studies

The purpose of this study is to assess the effectiveness and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn's disease over a period of 24 weeks and a follow-up period up to 52 weeks.

The purpose of this study is to evaluate the safety of using unlicensed cord blood units from the National Cord Blood Program in unrelated  patients needing stem cell transplants, by carefully documenting all infusion-related problems.

The purpose of this study is to collect fat and blood vessel wall tissue for processing into adult stem cells and then test those cells for specific biological markings.

The purpose of this study is to collect human menstrual blood at the time of gynecology visits in order to conduct future studies on the isolation and characterization of human menstrual blood and endometrial stem cells to better individualize treatment for abnormal uterine bleeding (AUB) and study the therapeutic properties of human menstrual-derived Mesenchymal Stem Cells (MSCs).

The purpose of this study is to assess optimal dosing frequency, effectiveness and safety of adipose-derived autologous mesenchymal stem cells delivered into the spinal fluid of patients with multipe system atrophy (MSA).

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. There is no available treatment to slow or halt disease progression. 

The purpose of this study is to explore patients’ perceptions using educational interventions to debunk or prebunk misinformation of advertisements about unproven stem cell interventions (SCIs). 

The purpose of this study to test the feasibility and safety for autologous (from your own body) skin cells that are manufactured into stem cells of cardiac lineage to be delivered into the heart muscle to determine if those stem cells will strengthen the heart muscle and can be used as an additional treatment for the management of  congenital heart disease. 

The purpose of this study is to assess the safety and tolerability of intravenously delivered mesenchymal steml cells (MSC) in one of two fixed dosing regimens at two time points in patients with chronic kidney disease.

The aim of this study is to measure the differences in quality of life and mood of hematopoietic stem cell transplant (HCT) patients and their caregivers staying at a hospital hospitality house (HHH), such as the Gift of Life Transplant House, the Help in Healing Home, and the Gabriel House of Care versus staying at a hotel/rental apartment or house. The goal is to investigate if staying in a HHH, with its different environment and support systems and programs, has a positive impact on the quality of life (QOL) and mood of patients undergoing a HCT and their caregivers.

The purpose of this study is to assess the effectiveness and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn's disease over a period of 24 weeks and a follow-up period up to 52 weeks.

The purpose of this study is to evaluate the long-term safety of a single dose of darvadstrocel in participants with Crohn's disease (CD) and complex perianal fistula by evaluation of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs).

The purpose of this study is to assess the safety and feasibility of mesenchymal stem cells therapy in patients with advanced chronic obstructive pulmonary disease.

The purpose of this study is to evaluate the pharmacokinetics (PK), safety and tolerability of pegcetacoplan in patients with TA-TMA.

The purpose of this study is to produce, using current Good Manufacturing Practices (cGMPs), a bank of 50 primary fibroblast cell lines from skin biopsies obtained by consenting donors who meet 21 CFR 1271 donor eligibility criteria, and to use fibroblasts in the cell bank generated in aim 1 to produce new induced pluripotent stem cell lines using Good Manufacturing Practices (cGMPs). These iPSC lines will then be screened to identify those with optimal characteristics for treatment purposes, as well as for the potential generation of transplantable tissues and therapeutics for chronic disease.

The purpose of this study is to determine the safety and feasibility of allogeneic, culture-expanded BM-MSCs in subjects with painful facet joint arthropathy.

The purpose of this study is to determine determine the safety of intraspinal delivery of mesenchymal stem cells (MSCs) to the cerebral spinal fluid of patients with Amyotrophic Lateral Sclerosis (ALS) using a dose-escalation study.

To determine the safety and toxicity of intra-arterial infused autologous adipose derived mesenchymal stromal (stem) cells in patients with vascular occlusive disease of the kidney.

The purpose of this study is to evaluate the effectiveness of ibrutinib in reducing the incidence of NIH moderate/severe chronic GVHD.

The purpose of this trial is to compare the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio. All participants will be followed for 72 months after randomization (Day 0, Visit 0).

The objective of this study is to evaluate the safety and feasibility of autologous mononuclear cells (MNC) collected from bone marrow (BM) delivered into the myocardium of the right ventricle of subjects with Ebstein anomaly undergoing surgical Ebstein repair. Additionally, the potential cardiovascular benefits will also be evaluated. This add-on procedure is anticipated to pose little risk to the subject and has the potential to foster a new strategy that leverages the regenerative capacity of individuals with congenital heart disease during the surgically mandated Ebstein repair.

This phase I/II trial studies the side effects and best dose of oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) infected mesenchymal stem cells and to see how well it works in treating patients with recurrent ovarian cancer. Mesenchymal stem cells may be able to carry tumor-killing substances directly to ovarian cancer cells.

To assess the safety and feasibility of mesenchymal stem cells therapy in patients with transplant related bronchiolitis obliteran syndrome (BOS).

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease. 

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation.  Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus.  Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of this study is to assess the safety of autologous mesenchymal stromal (stem) cell transfer using a biomatrix (the Gore Fistula Plug) to treat perianal fistula.

The overall goal of this study is to determine the safety and feasibility of infusing adipose-derived mesenchymal stem cells directly into the artery of renal allografts with biopsy-proven rejection in order to reduce inflammation detected in the graft.   We contend that future studies will show that administering immunomodulatory cells directly into the allograft will be more effective and safer than the current approaches of delivering massive doses of systemic immunosuppression.

Study participation involves receiving mesenchymal stem cells (MSC), created from the adipose tissue (body fat) of a donor, and infused into the main artery of a transplanted ...

The purpose of the present study is to investigate the safety and efficacy of a single intrathecal injection of autologous, culture expanded AD-MSCs specifically in subjects with severe traumatic SCI when compared to patients undergoing physical therapy.

The purpose of this study is to collect, convert and bank blood cells from healthy volunteers into stem cells (iPSCs) at a current good manufacturing practice (cGMP) facility within the Discovery and Innovation building on the Mayo FLorida campus. After comprehensive validation, we will bank those cGMP-iPSCs as a resource available to Mayo Clinic investigators and also to outside investigators as appropriate. Those bio-specimens could be unique resources to develop new protocols for production of clinical grade iPSC-derived cells, cell-derived products such as extracellular vesicles, and tissues to support Investigational New Drug (IND) and related clinical trials.

To compare the effect of senolytic drugs on cellular senescence, physical ability or frailty, and adipose tissue-derived MSC functionality in patients with chronic kidney disease. Primary Objectives: To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on clearing senescent adipose-derived MSC in patients with CKD. To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on improving adipose-derived MSC functionality in patients with CKD. Secondary Objective: To assess the short-term effect of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on ...

The investigators propose to study the safety of autologous mesenchymal stromal cell transfer using a biomatrix (the Gore Bio-A Fistula Plug) in a Phase I study using a single dose of 20 million cells. 20 patients (age 12 to 17 years) with Crohns perianal fistulas will be enrolled. Subjects will undergo standard adjuvant therapy including drainage of infection and placement of a draining seton. Six weeks post placement of the draining seton, the seton will be replaced with the MSC loaded Gore fistula plug as per current clinical practice. The subjects will be subsequently followed for fistula response and closure ...

The purpose of this study is to test the safety of this novel cell, combination- based regenerative therapy for use in patients with symptomatic focal cartilage defects of the knee.

This study aims to evaluate the safety of intramyocardial delivery of autologous umbilical cord blood-derived mononuclear cells during Fontan surgical palliation and measure surrogate markers of myocardial protection within a non-randomized study design to obtain prospective data from treatment and control populations.

The purpose of this study is to engage a cohort of patients who are avid information seekers about stem cells to assess their beliefs, online information sources and their credibility, and views on the credibility and persuasiveness of advertisements and warning messages available on the internet; we will use this data along with health behavior theories to develop communication messages aimed at inoculating patients against misinformation, correcting misconceptions, and providing evidence-based information about stem cell procedures.

The investigators propose to study the safety of autologous mesenchymal stromal cell transfer using a biomatrix (the Gore® Bio-A®; Fistula Plug) in a Phase I study using a single dose of 20 million cells. Twenty adult patients (age 18 years or older) with refractory, complicated perianal fistulizing Crohn's disease will be enrolled. Subjects will undergo standard adjuvant therapy including drainage of infection and placement of a draining seton with continuation of pre-existing anti-Crohn's therapy. Six weeks post placement of the draining seton, the seton will be replaced with the MSC loaded Gore® Bio-A® fistula plug as per current clinical practice. ...

In this proposal, we will generate hiPSCs from AA patients and use our TREE-based approaches to introduce AA-associated variants into isogenic hiPSCs. In turn, we will use these isogenic hiPSC lines in a 3-D cortical model to address the following hypothesis-testing questions: (1) Does the presence of specific ABCA7 variants modulate disease-related phenotypes in a hiPSC-based system? (2) Are the risk modifying effects of the ABCA7 variants mediated through cell-autonomous or non-autonomous mechanisms? (3) Do these ABCA7 variants exert their effects through modulation of Aβ processing, secretion, and uptake? (4) What is the effect of these ABCA7 variants ...

This study is an extension to re-treat partial and non-responders from the previously approved Phase 1 MCS-AFP protocols IRB #12-009716 (Crohn's Disease perianal fistulas) and 15-003200 (cryptoglandular perianal fistulas).

Group 1: The primary purpose of this study is to evaluate the safety and tolerability of an autologous dendritic cells (DC) vaccine delivered by intra-tumoral injection in patients with primary liver cancer treated with high-dose conformal external beam radiotherapy (EBRT).

Group 2: The primary purpose of this study is to estimate the progression-free survival rate at 2 years post-registration to see if treatment is efficacious compared to historical data

The purpose of this study is to determine the safety and efficacy of intrathecal treatment delivered to the cerebrospinal fluid (CSF) of mesenchymal stem cells in ALS patients every 3 months for a total of 4 injections over 12 months. Mesenchymal stem cells (MSCs) are a type of stem cell that can be grown into a number of different kinds of cells. In this study, MSCs will be taken from the subject's body fat and grown. CSF is the fluid surrounding the spine. The use of mesenchymal stem cells is considered investigational, which means it has not been approved by ...

The purpose of this study is to assess neurodevelopmental and psychosocial outcomes (i.e., executive function, social cognition, psychosocial adjustment, adaptive skills) in children with hypoplastic left heart syndrome (HLHS) who underwent right-ventricle-directed delivery of autologous umbilical cord derived mononuclear cells during staged cardiac surgical palliation, and to compare their outcomes to a matched sample of children with HLHS who did not receive autologous umbilical cord derived mononuclear cells during surgery.

The purpose of this study is to assess the safety, tolerability, optimal dosing, effectiveness signals reflecting kidney repair, and markers of mesenchymal stem cells (MSC) function that relate to response to allogenenic adipose tissue-derived MSC in patients with Chronic Kidney Disease (CKD).

Will injection(s) of autologous culture-expanded AMSCs be safe and efficacious for treatment of painful Hip OA, and if so, which dosing regimen is most effective?

The purpose of this study is to determine the safety of using an autologous mesenchymal stromal cell (MSC) coated fistula plug in people with fistulizing Crohn's disease. Autologous means these cells to coat the plug come from the patient.

The purpose of this study is to assess the safety and effectiveness of a Stem cell transfer using a biomatrix (The Gore Fistula Plug) in patients with persistent symptoms of post-surgical gastrointestinal leaks despite current standard radiologic and endoscopic treatments.  The subjects will be followed for fistula response and closure for 18 months. This is an autologous product (derived from the patient) and used only for the same patient.

The purpose of this study is to determine the safety and practical treatment use of STEM cells collected from a patient's own fat tissue, expanded in laboratory culture, and injected to treat symptoms of mild to severe knee osteoarthritis.

The purpose of this study is to determine whether AVB-114 compared to standard of care treatment is effective in inducing remission of the treated complex perianal fistula in subjects with Crohn’s Disease. It also aims to assess clinical and radiologic components of fistula remission, safety of treatment, disease activity, patient Quality of Life, and patient care journey, between AVB-114 and standard of care treatment.

The purpose of this study is to determine the success of mesenchymal stem cells, developed from the patient's own fat tissue, for reducing hemodialysis arteriovenous fistula failure when applied during the time of surgical creation.

The purpose of this study is to evaluate the safety and effectiveness of CD34+ cell intracoronary injections for treating coronary endothelial dysfunction (CED).

Ulcerative Colitis (UC) is a chronic inflammatory disease affecting the mucosal lining of the colon and rectum and the incidence is increasing, but the etiology remains unknown. Patients may require a proctocolectomy due to refractory disease. Prior to an operation, UC is treated with antibiotic therapy, immunomodulatory therapy and immunosuppressive agents. While there is an increasing number of approved biologics for the treatment of UC, there are many patients that still suffer from refractory disease. Thus, alternative mechanisms of therapy are desperately needed.

Treatments that have the potential to reduce mucosal inflammation could alleviate the pathology of luminal UC. This trial ...

The purpose of this study is to collect adipose tissue from patients undergoing elective surgery, or from healthy volunteers, test the donors to assure that they comply with all regulatory aspects required of healthy donors, expand and test mesenchymal stromal cells (MSC), and bank them for future use.

The objective of this study is to generate a panel of iPSCs from 30 subjects who do not have a personal history of major neuropsychiatric disorders.  

State-of-the-art induced pluripotent stem cells (iPSC) technology has become a powerful biomedical research tool and it clearly holds great potential for application to neuropsychiatric research.

This study will evaluate the safety of intramuscular administration of PLX-R18 (allogenetic ex-vivo explanded placental adherent stromal cells) in subjects who have with incomplete hematopoietic recovery after hematopoietic stem cell transplantation.

The current proposal aims to test the feasibility of immune function analysis for Tai Chi Easy (TCE) intervention in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) with concurrent exploration of health related quality of life (HRQOL).

The purpose of this study is to evaluate quality of life over time in patients treated with CAR-T therapy compared with autologous and allogeneic stem cell transplant.

The purpose of this study is to determine the effectiveness of MB-CART2019.1 cells administered following a conditioning lymphodepletion regimen in diffuse large B cell lymphoma (DLBCL) subjects who failed at least two lines of therapy as measured by objective response rate (ORR) at one month.

This phase Ib/II trial studies how well dendritic cell therapy after cryosurgery in combination with pembrolizumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Vaccines made from a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. Cryosurgery, also known as cryoablation or cryotherapy, kills tumor cells by freezing them. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving dendritic cell therapy after cryosurgery in combination with pembrolizumab may work better in treating patients ...

This is a double-blind, sham-controlled clinical study to evaluate the safety and feasibility of AMI MultiStem therapy in subjects who have had a heart attack (Non-ST elevation MI).

The purpose of this study is to evaluate safety, tolerability, pharmacokinetics, and effectiveness of SER-155 in adults undergoing hematopoietic stem cell transplantation to reduce the risk of infection and graft vs. host disease.

The purpose of this study is to compare the efficacy and safety of maribavir to valganciclovir for the treatment of cytomegalovirus (CMV) infection in asymptomatic hematopoietic stem cell transplant recipients.

The purpose of this study is to determine the safety of using an autologous mesenchymal stromal cell (MSC) coated fistula plug in people with rectovaginal fistulizing Crohn's disease. Autologous means that these cells that coat the plug come from you. You will be in this study for two years. There is potential to continue to monitor your progress with lifelong regular visits as part of your standard of care. All study visits take place at Mayo Clinic and Rochester, MN. The study visit schedule is as follows: Visit 1 (Week -6) - Screening visit: exam under anesthesia and surgery to ...

The purpose of this study is evaluate the safety of allogeneic adipose derived mesenchymal stem cell (AMSC) use during hemodialysis arteriovenous fistula and arterial bypass creation and its effectiveness on improving access maturation and primary anastomotic patency.

The purpose of this study is to evaluate the cellular composition of PRP produced by the Arthrex Angel System.

The purpose of this study is to evaluate the side effects of vaccine therapy in treating patients with glioblastoma that has come back. Vaccines made from a person's white blood cells mixed with tumor proteins from another person's glioblastoma tumors may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy may work better in treating patients with glioblastoma.

The purpose of this study is to compare standard-dose combination chemotherapy to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving ...

The purpose of this trial is to evaluate the cosmetic role of novel anti-aging regenerative skin care product, human platelet extract (HPE), on skin rejuvenation. 

Skin aging is a natural part of human aging process caused by intrinsic and extrinsic factors, such as genetics, cellular metabolism, chronic light exposure and other toxins.  Cosmetological care for facial skin aging includes daily skin care, correct sun protection and aesthetic non-invasive procedures. 80 participants over the age of 40 years with moderate photoaging (dyschromic facial skin with fine lines and wrinkles) will be recruited from Mayo Clinic Center for Aesthetic Medicine and ...

The purpose of this study is to collect adiopose tissue to derive mesenchymal stem cells.

Although survivorship recommendations have been developed in areas such as lymphoma and stem cell transplant, the long-term effects of CAR-T therapy are unknown. In addition, relatively little is known about the psychosocial impact of CAR-T on survivors and their caregivers. Due to the intensive nature of CAR-T treatment and its unique side effects, including neurotoxicity in the acute setting and infections and financial burden in the long-term setting, a longitudinal study that assesses these issues in a quantitative and qualitative fashion is required. Consideration of both patient and caregiver needs is important for the provision of appropriate and ...

The study aims to characterize patient factors, such as pre-existing comorbidities, cancer type and treatment, and demographic factors, associated with short- and long-term outcomes of COVID-19, including severity and fatality, in cancer patients undergoing treatment. The study also is aimed to describe cancer treatment modifications made in response to COVID-19, including dose adjustments, changes in symptom management, or temporary or permanent cessation. Lastely, evaluate the association of COVID-19 with cancer outcomes in patient subgroups defined by clinico-pathologic characteristics.

The primary objective of the United States Food and Drug Administration (FDA) for this study is to demonstrate non-inferiority in subjects who received an allogeneic BMT for subjects randomized to Rezafungin for Injection compared to subjects randomized to the standard antimicrobial regimen (SAR) for fungal-free survival at Day 90 (±7 days).

The primary objective of the European Medicines Agency (EMA) for this study is to demonstrate superiority in subjects who received an allogeneic BMT randomized to Rezafungin for Injection compared to subjects randomized to the SAR for fungal-free survival at Day 90 (±7 days).

The purpose of this study is to assess the feasibility and safety of delivering adipose mesenchymal stem cells (AMSCs) to kidney allografts.

The purpose of this study is to assess the safety, effectiveness, and overall benefit of FCR001 cell therapy in de novo living donor renal transplantation.

This randomized phase III trial studies rituximab after stem cell transplant and to see how well it works compared with rituximab alone in treating patients with in minimal residual disease-negative mantle cell lymphoma in first complete remission. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. ...

The purpose of this research study is to evaluate a treatment regimen called IRD which will be given to participants after their stem cell transplant in an effort to help prolong the amount of time the participants are disease-free after transplant. IRD is a three-drug regimen consisting of ixazomib, lenalidomide (also called Revlimid), and dexamethasone. After 4 cycles of IRD, the participants will be randomized to receive maintenance therapy either with ixazomib or lenalidomide. 09/23/2019: Upon review of the interim analysis that suggested inferior progression-free survival in the ixazomib maintenance arm, there will be no further randomizations into the ...

This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a ...

The primary purpose of this study is to identify the therapeutic effect of Adipose-Induced Regeneration (AIR) in radiation-induced skin injury of post-mastectomy breast cancer patients.

Mayo Clinic Footer

• Request Appointment
• About Mayo Clinic
• About This Site

Legal Conditions and Terms

• Terms and Conditions
• Privacy Policy
• Notice of Privacy Practices
• Notice of Nondiscrimination
• Manage Cookies

Advertising

Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any of the third party products and services advertised.

• Advertising and sponsorship policy
• Advertising and sponsorship opportunities

Reprint Permissions

A single copy of these materials may be reprinted for noncommercial personal use only. "Mayo," "Mayo Clinic," "MayoClinic.org," "Mayo Clinic Healthy Living," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research.

Viterbi Conversations in Ethics

Stem Cells: A Case for the Use of Human Embryos in Scientific Research

Embryonic stem cells have immense medical potential. While both their acquisition for and use in research are fraught with controversy, arguments against their usage are rebutted by showing that embryonic stem cells are not equivalent to human lives. It is then argued that not using human embryos is unethical. Finally, an alternative to embryonic stem cells is presented.

INTRODUCTION

Embryonic stem cells have the potential to cure nearly every disease and condition known to humanity. Stem cells are nature’s Transformers. They are small cells that can regenerate indefinitely, waiting to transform into a specialized cell type such as a brain cell, heart cell or blood cell [1]. Most stem cells form during the earliest stages of human development, immediately when an embryo is formed. These cells, known as embryonic stem cells (ESCs), eventually develop into every single type of cell in the body. As the embryo develops, adult stem cells (ASCs) replace these all-powerful embryonic stem cells. ASCs can only become a number of different cells within their potency. This limited application means an adult mesenchymal stem cell cannot become a neural cell.

By harnessing the unique ability of embryonic stem cells to transform into functional cells, scientists can develop treatments for a number of diseases and injuries, according to the California Institute for Regenerative Medicine, a private organization which awards grants for stem cell research [1]. For example, scientists at the Cleveland Clinic converted ESCs into heart muscle cells and injected them into patients who suffered from heart attacks. The cells continued to grow and helped the patients’ hearts recover [2].

With this enormous potential to cure devastating diseases, including heart failure, spinal cord injuries and Alzheimer’s disease, governments and research organizations have the moral imperative to support and encourage embryonic stem cell research. President Barack Obama signed an executive order in 2009 loosening federal funding restrictions on stem cell research, saying, “We will aim for America to lead the world in the discoveries it one day may yield.” [3]. The National Institute of Health and seven state governments, including California, Maryland and New York, followed Obama’s lead by creating programs that offered over $5 billion in funding and other incentives to scientists and research institutions for stem cell research [4].

A MIRACLE CURE

Scientists believe that harnessing the capability of embryonic stem cells will unlock the cure for countless diseases. “I am very excited about embryonic stem cells,” said Dr. Dieter Egli, professor of developmental cell biology at Columbia University. “They will lead to unprecedented discoveries that will transform life. I have no doubt about it.” [5]. The results thus far are inspiring. In 2016, Kris Boesen, a 21-year-old college student from Bakersfield, California, suffered a severe spinal cord injury in a car accident that left him paralyzed from the neck down. In a clinical trial conducted by Dr. Charles Liu at the University of Southern California Keck School of Medicine, Boesen was injected with 10 million embryonic stem cells that transformed into nerve cells [6]. Three months after the treatment, Boesen regained the use of his arms and hands. He could brush his teeth, operate a motorized wheelchair, and live more independently. “All I’ve wanted from the beginning was a fighting chance,” he said. The power of stem cells made his wish possible [6].

Embryonic stem cell treatments may also cure type 1 diabetes. Type 1 diabetes, which affects 42 million worldwide, is an autoimmune disorder that results in the destruction of insulin-producing beta cells found in the pancreas [7]. ViaCyte, a company in San Diego, California, is developing an implant that contains replacement beta cells originating from embryonic stem cells [7]. The implant will preserve or replace the original beta cells to protect them from the patient’s immune system [7]. The company believes that if successful, this strategy will effectively cure type 1 diabetes. Patients with the disease will no longer have to closely monitor their blood sugar levels and inject insulin [7]. ViaCyte projects that an experimental version of this implant will become available by 2020 [7].

Ultimately, scientists believe they will grow complex organs using stem cells within the next decade [8]. Over 115,000 people in the United States need a life-saving organ donation, and an average of 20 people die every day due to the lack of available organs for transplant, according to the American Transplant Foundation [9]. Three-dimensional printing of entire organs derived from stem cells holds the most promise for solving the organ shortage crisis [8]. Researchers at the University of California, San Diego have successfully printed part of a functional liver [8]. While the printed liver is not ready for transplant, it still performs the functions of a normal liver. This has helped scientists reduce the need for often cruel and unethical animal testing. The scientists expose drugs to the printed liver and observe how it reacts. The liver’s response closely mimics that of a human being’s and no living animals are harmed in the process [8].

HUMAN CELLS OR HUMAN LIFE?

Research using embryonic stems cells provides an unprecedented understanding of human development and the potential to cure devastating diseases. However, stem cell research has generated controversy among religious organizations such as the Catholic Church as well as the “pro-life” movement [3]. That is because scientists harvest stem cells from embryos donated by fertility clinics. Opponents of embryonicstem cell research equate the destruction of an embryo to the murder of an innocent human being [10]. Pope Benedict XVI said that harvesting stem cells is “not only devoid of the light of God but is also devoid of humanity” [3]. However, this view does not reflect a reasonable understanding and interpretation of basic biology. Researchers typically harvest embryonic stem cells from an embryo five days after fertilization [1]. At this stage, the entire embryo consists of less than 250 cells, smaller than the tip of a pin. Of these cells, only 30 are embryonic stem cells, which cannot perform any human function [11]. For comparison, an adult has more than 72 trillion cells, each with a specialized function [3]. Therefore, this microscopic blob of cells in no way represents human life.

With no functional cells, there exist no characteristics of a human being. Fundamentalist Christians believe that the presence or absence of a heartbeat signifies the beginning and end of a human life [10]. However, at this stage there is no heart, not even a single heart cell [10]. Some contend that brain activity, or the ability to feel, defines a human being. Michael Gazzaniga, president of the Cognitive Neuroscience Institute at the University of California, Santa Barbara, explains in his book,  The Ethical Brain,  that the “fertilized egg is a clump of cells with no brain.” [12]. There is no brain nor nerve cells that could allow this cellular object to interact with its environment [12]. The only uniquely human feature of embryonic cells at this stage is that they contain human DNA. This means that a 5-day-old human embryo is effectively no different than the Petri dishes of human cells that have grown in laboratories for decades with no controversy or opposition. Therefore, if the cluster of cells in the earliest stage of a human embryo is considered a “human life,” a growing plate of skin cells must also be considered “human life.” Few would claim that a Petri dish of human cells is morally equivalent to a living human or any other animal. Why, then, would a microscopic collection of embryonic cells have the same moral status as an adult human?

The status of the human embryo comes from its  potential  to turn into a fully grown human being.  However, the potential of this entity to become an individual does not logically mean that it has the same status as an individual who can think and feel. If this were true, virtually every cell grown in a laboratory would be subject to the same controversy. This is because scientists have developed technology to convert an ordinary cell such as a skin cell into an embryo [10]. Although this requires a laboratory with special conditions, the normal development of a human being also requires special conditions in the womb of the mother. Therefore, almost any cell could be considered a potential individual, so it is illogical to conclude that a cluster of embryonic cells deserves a higher moral status.

THE FATE OF UNUSED EMBRYOS

Hundreds of thousands of embryos are destroyed each year in a process known as in vitro fertilization (IVF), a popular procedure that helps couples have children [13]. Society has an ethical obligation to use these discarded embryos to make medical advancements rather than simply throw them in the trash for misguided ideological and religious reasons as opponents of embryonic stem cell research desire.

With IVF, a fertility clinician harvests sperm and egg cells from the parents and creates an embryo in a laboratory before implanting it in the woman’s womb. However, creating and implanting a single embryo is expensive and often leads to unsuccessful implantation. Instead, the clinician typically creates an average of seven embryos and selects the healthiest few to implant [13].

This leaves several unused embryos for every one implanted. The couple can pay a fee to preserve the unused embryos by freezing them or can donate them to another family. Otherwise, they are slated for destruction [14]. A 2011 study in the “Journal of the American Society for Reproductive Medicine” found that 19 percent of the unused embryos are discarded and only 3 percent are donated for scientific research [14]. Many of these embryos could never grow into a living person given the chance because they are not healthy enough to survive past early stages of development [14]. If a human embryo is already destined for destruction or has no chance of survival, scientists have the ethical imperative to use these embryos to research and develop medical treatments that could save lives. The modern version of the Hippocratic oath states, “I will apply, for the benefit of the sick, all measures which are required [to heal]” [10]. Republican Senator Orrin Hatch of Utah supports the pro-life movement, which recognizes early embryos as human individuals. However, even he favors using the leftover embryos for the greater good. “The morality of the situation dictates that these embryos, which are routinely discarded, be used to improve and save lives. The tragedy would be in not using these embryos to save lives when the alternative is that they would be discarded.” [3]

ALTERNATIVES TO EMBRYONIC STEM CELLS

Although scientists have used embryonic stem cells (ESCs) for promising treatments, they are not ideal, and scientists hope to eliminate the need for them. Primarily, ESCs come from an embryo with different DNA than the patient who will receive the treatment, meaning they are not autologous. ESCs are not necessarily compatible with everyone and could cause the immune system to reject the treatment [11]. The most promising alternative to ESCs are known as induced pluripotent stem cells. In 2008, scientists discovered a way to reprogram human skin cells to embryonic stem cells [15]. Scientists easily obtained these cells from a patient’s skin, converted them into the desired cell type, then transplanted them into the diseased organ without risk of immune rejection [15]. This eliminates any ethical concerns because no embryos are harvested or destroyed in the process. However, induced stem cells have their own risks. Recent studies have shown that they can begin growing out of control and turn into cancer [3]. Several of the first clinical trials with induced stem cells, including one aimed at curing blindness by regenerating a patient’s retinal cells, were halted because potentially cancerous mutations were detected [3].

Scientists believe that induced stem cells created in a laboratory will one day completely replace embryonic stem cells harvested from human embryos. However, the only way to create perfect replicas of ESCs is to thoroughly understand their structure and function. Scientists still do not completely understand how ESCs work. Why does a stem cell sometimes become a nerve cell, sometimes become a heart cell and other times regenerate to produce another stem cell? How can we tell a stem cell what type of cell to become? To develop a viable alternative to ESCs, scientists must first answer these questions with experiments on ESCs from human embryos. Therefore, extensive embryonic stem cell research today will eliminate the need for embryonic stem cells in the future.

The Biomedical Engineering Society Code of Ethics calls upon engineers to “use their knowledge, skills, and abilities to enhance the safety, health and welfare of the public.” [16] Stem cell research epitomizes this. Stem cells hold the cure for numerous diseases ranging from spinal cord injuries to organ failure and have the potential to transform modern medicine. Therefore, the donation of human embryos to scientific research falls within most conventional ethical frameworks and should be allowed with minimal restriction.

Because of widespread ignorance about the science behind stem cells, ill-informed opposition has prevented scientists from receiving the funding and support they need to save millions of lives. For example, George W. Bush’s religious opposition to stem cell research resulted in a 2001 law severely limiting government funding for such research [3]. Although most opponents of stem cell research compare the destruction of a human embryo to the death of a living human, the biology of these early embryos is no more human than a plate of skin cells in a laboratory. Additionally, all embryos sacrificed for scientific research would otherwise be discarded and provide no benefit to society. If society better understood the process and potential of embryonic stem cell research, more people would surely support it.

Within the next decade, stem cells will likely provide simple cures for diseases that are currently untreatable, such as Alzheimer’s disease and organ failure [1]. As long as scientists receive support for embryonic stem cell research, stem cell therapies will become commonplace in clinics and hospitals around the world. Ultimately, the fate of this new medical technology lies in the hands of the public, who must support propositions that will continue to allow and expand the impact of embryonic stem cell research.

By Jonathan Sussman, Viterbi School of Engineering, University of Southern California

ABOUT THE AUTHOR

At the time of writing this paper, Jonathan Sussman was a senior at the University of Southern California studying biomedical engineering with an emphasis in biochemistry. He was an undergraduate research assistant in the Graham Lab investigating proteomics of cancer cells and was planning to attend an MD/PhD program.

[1] “Stem Cell Information”,  Stem Cell Basics , 2016.  [Online]. Available at:  https://stemcells.nih.gov/info/basics/3.htm  [Accessed 11 Oct. 2018].

[2] Cleveland Clinic, “Stem Cell Therapy for Heart Disease | Cleveland Clinic”, 2017.  [Online]. Available at:  https://my.clevelandclinic.org/health/diseases/17508-stem-cell-therapy-for-heart-disease  [Accessed 14 Oct. 2018].

[3] B. Lo and L. Parham, “Ethical Issues in Stem Cell Research”,  Endocrine Reviews , 30(3), pp.204-213, 2009.

[4] G. Gugliotta, “Why Many States Now Have Stem Cell Research Programs”, 2015. [Online]. Available at:  http://www.governing.com/topics/health-human-services/last-decades-culture-wars-drove-some-states-to-fund-stem-cell-research.html  [Accessed 14 Oct. 2018].

[5] D. Cyranoski, “How human embryonic stem cells sparked a revolution”,  Nature Journal , 2018. [Online]. Available at:  https://www.nature.com/articles/d41586-018-03268-4  [Accessed 11 Oct. 2018].

[6] K. McCormack, “Young man with spinal cord injury regains use of hands and arms after stem cell therapy”, The Stem Cellar, 2016. [Online]. Available at:  https://blog.cirm.ca.gov/2016/09/07/young-man-with-spinal-cord-injury-regains-use-of-hands-and-arms-after-stem-cell-therapy/  [Accessed 11 Oct. 2018].

[7] A. Coghlan, “First implants derived from stem cells to ‘cure’ type 1 diabetes”,  New Scientist , 2017. [Online]. Available at:  https://www.newscientist.com/article/2142976-first-implants-derived-from-stem-cells-to-cure-type-1-diabetes/  [Accessed 11 Oct. 2018].

[8] C. Scott, “University of California San Diego’s 3D Printed Liver Tissue May Be the Closest We’ve Gotten to a Real Printed Liver”,  3DPrint.com | The Voice of 3D Printing / Additive Manufacturing , 2018. [Online]. Available at:  https://3dprint.com/118932/uc-san-diego-3d-printed-liver/  [Accessed 11 Oct. 2018].

[9] American Transplant Foundation, “Facts and Myths about Transplant”. [Online]. Available at:  https://www.americantransplantfoundation.org/about-transplant/facts-and-myths/  [Accessed 11 Oct. 2018].

[10] A. Siegel, “Ethics of Stem Cell Research”,  Stanford Encyclopedia of Philosophy , 2013. [Online]. Available at:  https://plato.stanford.edu/entries/stem-cells/  [Accessed 11 Oct. 2018].

[11] I. Hyun, “Stem Cells – The Hastings Center”,  The Hastings Center , 2018. [Online]. Available at:  https://www.thehastingscenter.org/briefingbook/stem-cells/  [Accessed 11 Oct. 2018].

[12] M. Gazzaniga, “The Ethical Brain”,  New York: Harper Perennial , 2006.

[13] M. Bilger, “Shocking Report Shows 2.5 Million Human Beings Created for IVF Have Been Killed | LifeNews.com”,  LifeNews , 2016. [Online]. Available at:  https://www.lifenews.com/2016/12/06/shocking-report-shows-2-5-million-human-beings-created-for-ivf-have-been-killed/  [Accessed 11 Oct. 2018].

[14] Harvard Gazette, “Stem cell lines created from discarded IVF embryos”, 2008. [Online]. Available at:  https://news.harvard.edu/gazette/story/2008/01/stem-cell-lines-created-from-discarded-ivf-embryos/  [Accessed 11 Oct. 2018].

[15] K. Murray, “Could we make babies from only skin cells?”, CNN, 2017. [Online]. Available at:  https://www.cnn.com/2017/02/09/health/embryo-skin-cell-ivg/index.html  [Accessed 11 Oct. 2018].

[16] Biomedical Engineering Society, “Biomedical Engineering Society Code of Ethics”, 2004. [Online]. Available at:  https://www.bmes.org/files/CodeEthics04.pdf  [Accessed 11 Oct. 2018].

• Open access
• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

555k Accesses

822 Citations

54 Altmetric

Metrics details

In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

Sukoyan MA, Vatolin SY, et al. Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies. Embryo Dev. 1993;36(2):148–58

Larijani B, Esfahani EN, Amini P, Nikbin B, Alimoghaddam K, Amiri S, Malekzadeh R, Yazdi NM, Ghodsi M, Dowlati Y, Sahraian MA, Ghavamzadeh A. Stem cell therapy in treatment of different diseases. Acta Medica Iranica. 2012:79–96 https://www.ncbi.nlm.nih.gov/pubmed/22359076 .

Sullivan S, Stacey GN, Akazawa C, et al. Quality guidelines for clinical-grade human induced pluripotent stem cell lines. Regenerative Med. 2018; https://doi.org/10.2217/rme-2018-0095 .

Amps K, Andrews PW, et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotechnol. 2011; 29 (12):1121–44.

Google Scholar  

Amit M, Itskovitz-Eldor J. Atlas of human pluripotent stem cells: derivation and culturing. New York: Humana Press; 2012.

Ludwig TE, Bergendahl V, Levenstein ME, Yu J, Probasco MD, Thomson JA. Feeder-independent culture of human embryonic stem cells. Nat Methods. 2006;3:637–46.

CAS   PubMed   Google Scholar  

Kang MI. Transitional CpG methylation between promoters and retroelements of tissue-specific genes during human mesenchymal cell differentiation. J. Cell Biochem. 2007;102:224–39.

Vaes B, Craeye D, Pinxteren J. Quality control during manufacture of a stem cell therapeutic. BioProcess Int. 2012;10:50–5.

Bloushtain-Qimron N. Epigenetic patterns of embryonic and adult stem cells. Cell Cycle. 2009;8:809–17.

Brindley DA. Peak serum: implications of serum supply for cell therapy manufacturing. Regenerative Medicine. 2012;7:809–17.

Solter D, Knowles BB. Immunosurgery of mouse blastocyst. Proc Natl Acad Sci U S A. 1975;72:5099–102.

CAS   PubMed   PubMed Central   Google Scholar  

Hoepfl G, Gassmann M, Desbaillets I. Differentiating embryonic stem cells into embryoid bodies. Methods Mole Biol. 2004;254:79–98 https://doi.org/10.1385/1-59259-741-6:079 .

Lim WF, Inoue-Yokoo T, Tan KS, Lai MI, Sugiyama D. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells. Stem Cell Res Ther. 2013;4(3):71. https://doi.org/10.1186/scrt222 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Mohr JC, de Pablo JJ, Palecek SP. 3-D microwell culture of human embryonic stem cells. Biomaterials. 2006;27(36):6032–42. https://doi.org/10.1016/j.biomaterials.2006.07.012 .

Article   CAS   PubMed   Google Scholar  

Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of the visceral yolk sac, blood islands, and myocardium. J Embryol Exp Morphol. 1985;87:27–45.

Kurosawa HY. Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells. J Biosci Bioeng. 2007;103:389–98.

Heins N, Englund MC, Sjoblom C, Dahl U, Tonning A, Bergh C, Lindahl A, Hanson C, Semb H. Derivation, characterization, and differentiation of human embryonic stem cells. Stem Cells. 2004;22:367–76.

Rosowski KA, Mertz AF, Norcross S, Dufresne ER, Horsley V. Edges of human embryonic stem cell colonies display distinct mechanical properties and differentiation potential. Sci Rep. 2015;5:Article number:14218.

PubMed   Google Scholar  

Chung Y, Klimanskaya I, Becker S, Li T, Maserati M, Lu SJ, Zdravkovic T, Ilic D, Genbacev O, Fisher S, Krtolica A, Lanza R. Human embryonic stem cell lines generated without embryo destruction. Cell Stem Cell. 2008;2:113–7.

Zhang X, Stojkovic P, Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M. Derivation of human embryonic stem cells from developing and arrested embryos. Stem Cells. 2006;24:2669–76.

Beers J, Gulbranson DR, George N, Siniscalchi LI, Jones J, Thomson JA, Chen G. Passaging and colony expansion of human pluripotent stem cells by enzyme-free dissociation in chemically defined culture conditions. Nat Protoc. 2012;7:2029–40.

Ellerström C, Hyllner J, Strehl R. single cell enzymatic dissociation of human embryonic stem cells: a straightforward, robust, and standardized culture method. In: Turksen K, editor. Human embryonic stem cell protocols. Methods in molecular biology: Humana Press; 2009. p. 584.

Heng BC, Liu H, Ge Z, Cao T. Mechanical dissociation of human embryonic stem cell colonies by manual scraping after collagenase treatment is much more detrimental to cellular viability than is trypsinization with gentle pipetting. Biotechnol Appl Biochem. 2010;47(1):33–7.

Ellerstrom C, Strehl R, Noaksson K, Hyllner J, Semb H. Facilitated expansion of human embryonic stem cells by single-cell enzymatic dissociation. Stem Cells. 2007;25:1690–6.

Brimble SN, Zeng X, Weiler DA, Luo Y, Liu Y, Lyons IG, Freed WJ, Robins AJ, Rao MS, Schulz TC. Karyotypic stability, genotyping, differentiation, feeder-free maintenance, and gene expression sampling in three human embryonic stem cell lines deri. Stem Cells Dev. 2004;13:585–97.

Watanabe K, Ueno M, Kamiya D, Nishiyama A, Matsumura M, Wataya T, Takahashi JB, Nishikawa S, Nishikawa S, Muguruma K, Sasai Y. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol. 2007;25:681–6.

Nie Y, Walsh P, Clarke DL, Rowley JA, Fellner T. Scalable passaging of adherent human pluripotent stem cells. 2014. https://doi.org/10.1371/journal.pone.0088012 .

Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.

Martin MJ, Muotri A, Gage F, Varki A. Human embryonic stem cellsexpress an immunogenic nonhuman sialic acid. Nat. Med. 2005;11:228–32.

Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988;336(6200):688–90. https://doi.org/10.1038/336688a0 .

Xu C, Inokuma MS, Denham J, Golds K, Kundu P, Gold JD, Carpenter MK. Feeder-free growth of undifferentiated human embryonic stem cells. Nature Biotechnol. 2001;19:971–4. https://doi.org/10.1038/nbt1001-971 .

Article   CAS   Google Scholar  

Weathersbee PS, Pool TB, Ord T. Synthetic serum substitute (SSS): a globulin-enriched protein supplement for human embryo culture. J. Assist Reprod Genet. 1995;12:354–60.

Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, Smuga-Otto K, Howden SE, Diol NR, Propson NE, Wagner R, Lee GO, Antosiewicz-Bourget J, Teng JM, Thomson JA. Chemically defined conditions for human iPSC derivation and culture. Nat. Methods. 2011;8:424–9.

Sommer CA, Mostoslavsky G. Experimental approaches for the generation of induced pluripotent stem cells. Stem Cell Res Ther. 2010;1:26.

PubMed   PubMed Central   Google Scholar  

Takahashi K, Yamanaka S. Induced pluripotent stem cells in medicine and biology. Development. 2013;140(12):2457–61 https://doi.org/10.1242/dev.092551 .

Shi D, Lu F, Wei Y, et al. Buffalos ( Bubalus bubalis ) cloned by nuclear transfer of somatic cells. Biol. Reprod. 2007;77:285–91. https://doi.org/10.1095/biolreprod.107.060210 .

Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. Development. 1962;10:622–40 http://dev.biologists.org/content/10/4/622 .

CAS   Google Scholar  

Kain K. The birth of cloning: an interview with John Gurdon. Dis Model Mech. 2009;2(1–2):9–10. https://doi.org/10.1242/dmm.002014 .

Article   PubMed Central   Google Scholar  

Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987;24(51(6)):987–1000.

Quinlan AR, Boland MJ, Leibowitz ML, et al. Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming. Cell Stem Cell. 2011;9(4):366–73.

Maherali N, Sridharan R, Xie W, Utika LJ, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell. 2007;1:55–70.

Ohi Y, Qin H, Hong C, Blouin L, Polo JM, Guo T, Qi Z, Downey SL, Manos PD, Rossi DJ, Yu J, Hebrok M, Hochedlinger K, Costello JF, Song JS, Ramalho-Santos M. Incomplete DNA methylation underlines a transcriptional memory of somatic cells in human IPS cells. Nat Cell Biol. 2011;13:541–9.

Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455:627–32 https://doi.org/10.1038/nature07314 .

Hilfiker A, Kasper C, Hass R, Haverich A. Mesenchymal stem cells and progenitor cells in connective tissue engineering and regenerative medicine: is there a future for transplantation? Langenbecks Arch Surg. 2011;396:489–97.

Zhang Wendy, Y., de Almeida Patricia, E., and Wu Joseph, C. Teratoma formation: a tool for monitoring pluripotency in stem cell research. StemBook, ed. The Stem Cell Research Community . June 12, 2012. https://doi.org/10.3824/stembook.1.53.1 .

Narsinh KH, Sun N, Sanchez-Freire V, et al. Single cell transcriptional profiling reveals heterogeneity of human induced pluripotent stem cells. J Clin Invest. 2011;121(3):1217–21.

Gertow K, Przyborski S, Loring JF, Auerbach JM, Epifano O, Otonkoski T, Damjanov I, AhrlundRichter L. Isolation of human embryonic stem cell-derived teratomas for the assessment of pluripotency. Curr Protoc Stem Cell Biol . 2007, Chapter 1, Unit 1B 4. 3: 1B.4.1-1B.4.29.

Cooke MJ, Stojkovic M, Przyborski SA. Growth of teratomas derived from human pluripotent stem cells is influenced by the graft site. Stem Cells Dev. 2006;15(2):254–9.

Przyborski SA. Differentiation of human embryonic stem cells after transplantation in immune-deficient mice. Stem Cells. 2005;23:1242–50.

Tannenbaum SE, Turetsky TT, Singer O, Aizenman E, Kirshberg S, Ilouz N, Gil Y, Berman-Zaken Y, Perlman TS, Geva N, Levy O, Arbell D, Simon A, Ben-Meir A, Shufaro Y, Laufer N, Reubinoff BE. Derivation of xeno-free and GMP-grade human embryonic stem cells- platforms for future clinical applications. PLoS One. 2012;7:e35325.

Cohen DE, Melton D. Turning straw into gold: directing cell fate for regenerative medicine. Nat Rev Genet. 2011;12:243–52.

Hwang NS, Varghese S, Elisseeff J. Controlled differentiation of stem cells. Adv Drug Deliv Rev. 2007;60(2):199–214. https://doi.org/10.1016/j.addr.2007.08.036 .

Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29.

Rao TP, Kuhl M. An updated overview on Wnt signaling pathways: a prelude for more. Circ Res. 2010;106:1798–806.

Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Development. 2009;136:3699–714.

Efthymiou AG, Chen G, Rao M, Chen G, Boehm M. Self-renewal and cell lineage differentiation strategies in human embryonic stem cells and induced pluripotent stem cells. Expert Opin Biol Ther. 2014;14:1333–44.

Yang L, Soonpaa MH, Adler ED, Roepke TK, Kattman SJ, Kennedy M, Henckaerts E, Bonham K, Abbott GW, Linden RM, Field LJ, Keller GM. Human cardiovascular progenitor cells develop from a KDRþembryonic-stem-cell-derived population. Nature. 2008;453:524–8.

Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, Agulnick AD, D’amour KA, Carpenter MK, Baetge EE. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26(4):443–52. https://doi.org/10.1038/nbt1393 .

Vallier L, Reynolds D, Pedersen RA. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev Biol. 2004;275:403–21.

Burridge PW, Zambidis ET. Highly efficient directed differentiation of human induced pluripotent stem cells into cardiomyocytes. Methods Mol Biol. 2013;997:149–61.

Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, Meng S, Chen Y, Zhou R, Song X, Guo Y, Ding M, Deng H. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology. 2007;45:1229–39.

Takasato M, Er PX, Becroft M, Vanslambrouck JM, Stanley EG, Elefanty AG, Little MH. Directing human embryonic stem cell differentiation towards a renal lineage generates a selforganizing kidney. Nat Cell Biol. 2014;16:118–26.

Huang SX, Islam MN, O’Neill J, Hu Z, Yang YG, Chen YW, Mumau M, Green MD, VunjakNovakovic G, Bhattacharya J, Snoeck HW. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat Biotechnol. 2014;32:84–91.

Kadzik RS, Morrisey EE. Directing lung endoderm differentiation in pluripotent stem cells. Cell Stem Cell. 2012;10:355–61.

Wichterle H, Lieberam I, Porter JA, Jessell TM. Directed differentiation of embryonic stem cells into motor neurons. Cell. 2002;110:385–97.

Spence JR, Mayhew CN, Rankin SA, Kuhar MF, Vallance JE, Tolle K, Hoskins EE, Kalinichenko VV, Wells SI, Zorn AM, Shroyer NF, Wells JM. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011;470:105–9.

Oldershaw RA, Baxter MA, Lowe ET, Bates N, Grady LM, Soncin F, Brison DR, Hardingham TE, Kimber SJ. Directed differentiation of human embryonic stem cells toward chondrocytes. Nat Biotechnol. 2010;28:1187–94.

Jun Cai, Ann DeLaForest, Joseph Fisher, Amanda Urick, Thomas Wagner, Kirk Twaroski, Max Cayo, Masato Nagaoka, Stephen A Duncan. Protocol for directed differentiation of human pluripotent stem cells toward a hepatocyte fate. 2012. DOI: https://doi.org/10.3824/stembook.1.52.1 .

Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H, Bumcrot D, Wang FY, Jones S, Shulok J, Rubin LL, Porter JA. Small-molecule modulators of hedgehog signaling: identification and characterization of smoothened agonists and antagonists. J Biol. 2002;1:10.

Oshima K, Shin K, Diensthuber M, Peng AW, Ricci AJ, Heller S. Mechanosensitive hair celllike cells from embryonic and induced pluripotent stem cells. Cell. 2010;141:704–16.

Osakada F, Jin ZB, Hirami Y, Ikeda H, Danjyo T, Watanabe K, Sasai Y, Takahashi M. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction. J Cell Sci. 2009;122:3169–79.

Kshitiz PJ, Kim P, Helen W, Engler AJ, Levchenko A, Kim DH. Control of stem cell fate and function by engineering physical microenvironments. Intergr Biol (Camb). 2012;4:1008–18.

Amps K, Andrews PW, Anyfantis G, Armstrong L, Avery S, Baharvand H, Baker J, Baker D, Munoz MB, Beil S, Benvenisty N, Ben-Yosef D, Biancotti JC, Bosman A, Brena RM, Brison D, Caisander G, Camarasa MV, Chen J, ChiaoE CYM, Choo AB, Collins D, et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat Biotechnol. 2011;29:1132–44.

Nukaya D, Minami K, Hoshikawa R, Yokoi N, Seino S. Preferential gene expression and epigenetic memory of induced pluripotent stem cells derived from mouse pancreas. Genes Cells. 2015;20:367–81.

Murdoch A, Braude P, Courtney A, Brison D, Hunt C, Lawford-Davies J, Moore H, Stacey G, Sethe S, Procurement Working Group Of National Clinical H, E. S. C. F, National Clinical H, E. S. C. F. The procurement of cells for the derivation of human embryonic stem cell lines for therapeutic use: recommendations for good practice. Stem Cell Rev. 2012;8:91–9.

Hewitson H, Wood V, Kadeva N, Cornwell G, Codognotto S, Stephenson E, Ilic D. Generation of KCL035 research grade human embryonic stem cell line carrying a mutation in HBB gene. Stem Cell Res. 2016;16:210–2.

Daley GQ, Hyun I, Apperley JF, Barker RA, Benvenisty N, Bredenoord AL, Breuer CK, Caulfield T, Cedars MI, Frey-Vasconcells J, Heslop HE, Jin Y, Lee RT, Mccabe C, Munsie M, Murry CE, Piantadosi S, Rao M, Rooke HM, Sipp D, Studer L, Sugarman J, et al. Setting global standards for stem cell research and clinical translation: the 2016 ISSCR guidelines. Stem Cell Rep. 2016;6:787–97.

Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. https://doi.org/10.1016/j.cell.2006.07.024 .

Loh YH, Wu Q, Chew JL, Vega VB, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet. 2006;38:431–40.

Menasche P, Vanneaux V, Hagege A, Bel A, Cholley B, Cacciapuoti I, Parouchev A, Benhamouda N, Tachdjian G, Tosca L, Trouvin JH, Fabreguettes JR, Bellamy V, Guillemain R, SuberbielleBoissel C, Tartour E, Desnos M, Larghero J. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. Eur Heart J. 2015;36:2011–7.

Schwartz SD, Regillo CD, Lam BL, Eliott D, Rosenfeld PJ, Gregori NZ, Hubschman JP, Davis JL, Heilwell G, Spirn M, Maguire J, Gay R, Bateman J, Ostrick RM, Morris D, Vincent M, Anglade E, Del Priore LV, Lanza R. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385:509–16.

Ilic D, Ogilvie C. Concise review: human embryonic stem cells-what have we done? What are we doing? Where are we going? Stem Cells. 2017;35:17–25.

Rocha V, et al. Clinical use of umbilical cord blood hematopoietic stem cells. Biol Blood Marrow Transplant. 2006;12(1):34–4.

Longo UG, Ronga M, Maffulli N. Sports Med Arthrosc 17:112–126. Achilles tendinopathy. Sports Med Arthrosc. 2009;17:112–26.

Tempfer H, Lehner C, Grütz M, Gehwolf R, Traweger A. Biological augmentation for tendon repair: lessons to be learned from development, disease, and tendon stem cell research. In: Gimble J, Marolt D, Oreffo R, Redl H, Wolbank S, editors. Cell engineering and regeneration. Reference Series in Biomedical Engineering. Cham: Springer; 2017.

Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626–34.

Widuchowski W, Widuchowski J, Trzaska T. Articular cartilage defects: study of 25,124 knee arthroscopies. Knee. 2007;14:177–82.

Li R, Lin Q-X, Liang X-Z, Liu G-B, et al. Stem cell therapy for treating osteonecrosis of the femoral head: from clinical applications to related basic research. Stem Cell Res Therapy. 2018;9:291 https://doi.org/10.1186/s13287-018-1018-7 .

Gangji V, De Maertelaer V, Hauzeur JP. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: five year follow-up of a prospective controlled study. Bone. 2011;49(5):1005–9.

Zhao D, Cui D, Wang B, Tian F, Guo L, Yang L, et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. 2012;50(1):325–30.

Sen RK, Tripathy SK, Aggarwal S, Marwaha N, Sharma RR, Khandelwal N. Early results of core decompression and autologous bone marrow mononuclear cells instillation in femoral head osteonecrosis: a randomized control study. J Arthroplast. 2012;27(5):679–86.

Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N, Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, Lemaitre JM. Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev. 2011;25:2248–53.

Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010;464:520–8.

Petkovich DA, Podolskiy DI, Lobanov AV, Lee SG, Miller RA, Gladyshev VN. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. 2017;25:954–60 https://doi.org/10.1016/j.cmet.2017.03.016 .

Gerontology, Rejuvenation by cell reprogramming: a new horizon in. Rodolfo G. Goya, Marianne Lehmann, Priscila Chiavellini, Martina Canatelli-Mallat, Claudia B. Hereñú and Oscar A. Brown. Stem Cell Res Therapy . 2018, 9:349. https://doi.org/10.1186/s13287-018-1075-y .

Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JLXJ, Rodriguez-Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P, Izpisua. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell. 2016;167:1719–33.

de Lázaro I, Cossu G, Kostarelos K. Transient transcription factor (OSKM) expression is key towards clinical translation of in vivo cell reprogramming. EMBO Mol Med. 2017;9:733–6.

Sun S, Li ZQ, Glencer P, Cai BC, Zhang XM, Yang J, Li XR. Bringing the age-related macular degeneration high-risk allele age-related maculopathy susceptibility 2 into focus with stem cell technology. Stem Cell Res Ther. 2017;8:135 https://doi.org/10.1186/s13287-017-0584-4 .

Liu J. Induced pluripotent stem cell-derived neural stem cells: new hope for stroke? Stem Cell Res Ther. 2013;4:115 https://doi.org/10.1186/scrt326 .

Shahjalal HM, Dayem AA, Lim KM, Jeon TI, Cho SG. Generation of pancreatic β cells for treatment of diabetes: advances and challenges. Stem Cell ResTher. 2018;9:355 https://doi.org/10.1186/s13287-018-1099-3 .

Kroon E, Martinson LA, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol. 2008;26;443–52.

Arora V, Pooja A, Munshi AK. Banking stem cells from human exfoliated deciduous teeth. J Clin Pediatr Dent. 2009;33(4):289–94.

Mao JJ. Stem cells and the future of dental care. New York State Dental J. 2008;74(2):21–4.

Reznick, Jay B. Continuing education: stem cells: emerging medical and dental therapies for the dental Professional. Dentaltown Magazine . 2008, pp. 42–53.

Arthur A, Rychkov G, Shi S, Koblar SA, Gronthos S. Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells. 2008;26(7):1787–95.

Cordeiro MM, Dong Z, Kaneko T, Zhang Z, Miyazawa M, Shi S, Smith A. Dental pulp tissue engineering with stem cells from exfoliated. J Endod. 2008;34(8):962–9.

Hayashi K, Ohta H, Kurimoto K, Aramaki S, Saitou M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell. 2011;146(4):519–32. https://doi.org/10.1016/j.cell.2011.06.052 .

Sadri-Ardekani H, Atala A. Testicular tissue cryopreservation and spermatogonial stem cell transplantation to restore fertility: from bench to bedside. Stem Cell ResTher. 2014;5:68 https://doi.org/10.1186/scrt457 .

Zhang Q, Xu M, Yao X, Li T, Wang Q, Lai D. Human amniotic epithelial cells inhibit granulosa cell apoptosis induced by chemotherapy and restore the fertility. Stem Cell Res Ther. 2015;6:152 https://doi.org/10.1186/s13287-015-0148-4 .

Ma DK, Bonaguidi MA, Ming GL, Song H. Adult neural stem cells in the mammalian central nervous system. Cell Res. 2009;19:672–82. https://doi.org/10.1038/cr.2009.56 .

Dantuma E, Merchant S, Sugaya K. Stem cells for the treatment of neurodegenerative diseases. Stem Cell ResTher. 2010;1:37 https://doi.org/10.1186/scrt37 .

Wang Q, Matsumoto Y, Shindo T, Miyake K, Shindo A, Kawanishi M, Kawai N, Tamiya T, Nagao S. Neural stem cells transplantation in cortex in a mouse model of Alzheimer’s disease. J Med Invest. 2006;53:61–9. https://doi.org/10.2152/jmi.53.61 .

Article   PubMed   Google Scholar  

Moghadam FH, Alaie H, Karbalaie K, Tanhaei S, Nasr Esfahani MH, Baharvand H. Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats. Differentiation. 2009;78:59–68. https://doi.org/10.1016/j.diff.2009.06.005 .

Byrne JA. Developing neural stem cell-based treatments for neurodegenerative diseases. Stem Cell ResTher. 2014;5:72. https://doi.org/10.1186/scrt461 .

Awe JP, Lee PC, Ramathal C, Vega-Crespo A, Durruthy-Durruthy J, Cooper A, Karumbayaram S, Lowry WE, Clark AT, Zack JA, Sebastiano V, Kohn DB, Pyle AD, Martin MG, Lipshutz GS, Phelps PE, Pera RA, Byrne JA. Generation and characterization of transgene-free human induced pluripotent stem cells and conversion to putative clinical-grade status. Stem Cell Res Ther. 2013;4:87. https://doi.org/10.1186/scrt246 .

Peng J, Zeng X. The role of induced pluripotent stem cells in regenerative medicine: neurodegenerative diseases. Stem Cell ResTher. 2011;2:32. https://doi.org/10.1186/scrt73 .

Wright BL, Barker RA. Established and emerging therapies for Huntington’s disease. 2007;7(6):579–87 https://www.ncbi.nlm.nih.gov/pubmed/17896994/579-87 .

Lin NH, Gronthos S, Bartold PM. Stem cells and periodontal regeneration. Aust Dent J. 2008;53:108–21.

Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, et al. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004;364:149–55.

Ramseier CA, Abramson ZR, Jin Q, Giannobile WV. Gene therapeutics for periodontal regenerative medicine. Dent Clin North Am. 2006;50:245–63.

Shi S, Bartold PM, Miura M, Seo BM, Robey PG, Gronthos S. The efficacy of mesenchymal stem cells to regenerate and repair dental structures. OrthodCraniofac Res. 2005;8:191–9.

Iohara K, Nakashima M, Ito M, Ishikawa M, Nakasima A, Akamine A. Dentin regeneration by dental pulp stem cell therapy with recombinant human bone morphogenetic protein. J Dent Res. 2004;83:590–5.

Hu B, Unda F, Bopp-Kuchler S, Jimenez L, Wang XJ, Haikel Y, et al. Bone marrow cells can give rise to ameloblast-like cells. J Dent Res. 2006;85:416–21.

Liu Y, Liu W, Hu C, Xue Z, Wang G, Ding B, Luo H, Tang L, Kong X, Chen X, Liu N, Ding Y, Jin Y. MiR-17 modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis. Stem Cells. 2011;29(11):1804–16. https://doi.org/10.1002/stem.728 .

Raspini G, Wolff J, Helminen M, Raspini G, Raspini M, Sándor GK. Dental stem cells harvested from third molars combined with bioactive glass can induce signs of bone formation in vitro. J Oral Maxillofac Res. 2018;9(1):e2. Published 2018 Mar 31. https://doi.org/10.5037/jomr.2018.9102 .

Christodoulou I, Goulielmaki M, Devetzi M, Panagiotidis M, Koliakos G, Zoumpourlis V. Mesenchymal stem cells in preclinical cancer cytotherapy: a systematic review. Stem Cell Res Ther. 2018;9(1;336). https://doi.org/10.1186/s13287-018-1078-8 .

Bansal R, Jain A. Current overview on dental stem cells applications in regenerative dentistry. J Nat Sci Biol Med. 2015;6(1):29–34. https://doi.org/10.4103/0976-9668.149074 .

Article   PubMed   PubMed Central   Google Scholar  

Edgar Ledesma-Martínez, Víctor Manuel Mendoza-Núñez, Edelmiro Santiago-Osorio. Mesenchymal stem cells derived from dental pulp: a review. Stem Cells Int . 2016, 4,709,572, p. doi: https://doi.org/10.1155/2016/4709572 ].

Grzech-Leśniak K. Making use of lasers in periodontal treatment: a new gold standard? Photomed Laser Surg. 2017;35(10):513–4.

Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG, Shi S. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100(10):5807–12. https://doi.org/10.1073/pnas.0937635100 .

Yasui T, Mabuchi Y, Toriumi H, Ebine T, Niibe K, Houlihan DD, Morikawa S, Onizawa K, Kawana H, Akazawa C, Suzuki N, Nakagawa T, Okano H, Matsuzaki Y. Purified human dental pulp stem cells promote osteogenic regeneration. J Dent Res. 2016;95(2):206–14. https://doi.org/10.1177/0022034515610748 .

Yamamoto A, Sakai K, Matsubara K, Kano F, Ueda M. Multifaceted neuro-regenerative activities of human dental pulp stem cells for functional recovery after spinal cord injury. Neurosci Res. 2014;78:16–20. https://doi.org/10.1016/j.neures.2013.10.010 .

d’Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A, Desiderio V, Laino G, Papaccio G. Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur Cell Mater. 2009;12, PMID: 19908196:75–83.

Wang L, Shen H, Zheng W, Tang L, Yang Z, Gao Y, Yang Q, Wang C, Duan Y, Jin Y. Characterization of stem cells from alveolar periodontal ligament. Tissue Eng. Part A. 2011;17(7–8):1015–26. https://doi.org/10.1089/ten.tea.2010.0140 .

Iwata T, Yamato M, Zhang Z, Mukobata S, Washio K, Ando T, Feijen J, Okano T, Ishikawa I. Validation of human periodontal ligament-derived cells as a reliable source for cytotherapeutic use. J Clin Periodontol. 2010;37(12):1088–99. https://doi.org/10.1111/j.1600-051X.2010.01597.x .

Chen F-M, Gao L-N, Tian B-M, Zhang X-Y, Zhang Y-J, Dong G-Y, Lu H, et al. Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: a randomized clinical trial. Stem Cell Res Ther. 2016;7:33. https://doi.org/10.1186/s13287-016-0288-1 .

Bakopoulou A, Leyhausen G, Volk J, Tsiftsoglou A, Garefis P, Koidis P, Geurtsen W. Comparative analysis of in vitro osteo/odontogenic differentiation potential of human dental pulp stem cells (DPSCs) and stem cells from the apical papilla (SCAP). Arch Oral Biol. 2011;56(7):709–21. https://doi.org/10.1016/j.archoralbio.2010.12.008 .

Han C, Yang Z, Zhou W, Jin F, Song Y, Wang Y, Huo N, Chen L, Qian H, Hou R, Duan Y, Jin Y. Periapical follicle stem cell: a promising candidate for cementum/periodontal ligament regeneration and bio-root engineering. Stem Cells Dev. 2010;19(9):1405–15. https://doi.org/10.1089/scd.2009.0277 .

Luan X, Ito Y, Dangaria S, Diekwisch TG. Dental follicle progenitor cell heterogeneity in the developing mouse periodontium. Stem Cells Dev. 2006;15(4):595–608. https://doi.org/10.1089/scd.2006.15.595 .

Handa K, Saito M, Tsunoda A, Yamauchi M, Hattori S, Sato S, Toyoda M, Teranaka T, Narayanan AS. Progenitor cells from dental follicle are able to form cementum matrix in vivo. Connect Tissue Res. 2002;43(2–3):406–8 PMID: 12489190.

Guo W, Chen L, Gong K, Ding B, Duan Y, Jin Y. Heterogeneous dental follicle cells and the regeneration of complex periodontal tissues. Tissue Engineering. Part A. 2012;18(5–6):459–70 https://doi.org/10.1089/ten.tea.2011.0261 .

Bai, Yudi et al. Cementum- and periodontal ligament-like tissue formation by dental follicle cell sheets co-cultured with Hertwig’s epithelial root sheath cells. Bone. 2011, 48, Issue 6, pp. 1417–1426, https://doi.org/10.1016/j.bone.2011.02.016 .

Cordeiro MM, Dong Z, Kaneko T, Zhang Z, Miyazawa M, Shi S, et al. Dental pulp tissue engineering with stem cells from exfoliated deciduous teeth. 2008, 34, pp. 962–969.

Dobie K, Smith G, Sloan AJ, Smith AJ. Effects of alginate, hydrogels and TGF-beta 1 on human dental pulp repair in vitro. Connect Tissue Res 2. 2002;43:387–90.

Friedlander LT, Cullinan MP, Love RM. Dental stem cells and their potential role in apexogenesis and apexification. Int Endod J. 2009;42:955–62.

Cai J, Zhang Y, Liu P, Chen S, Wu X, Sun Y, Li A, Huang K, Luo R, Wang L, Liu Y, Zhou T, Wei S, Pan G, Pei D, Generation of tooth-like structures from integration-free human urine induced pluripotent stem cells. Cell Regen (Lond). July 30, 2013, 2(1), pp. 6, doi: https://doi.org/10.1186/2045-9769-2-6 .

Craig J. Taylor, Eleanor M. Bolton, and J. Andrew Bradley 2011 Aug 12 and https://doi.org/10.1098/rstb.2011.0030 ], 366(1575): 2312–2322. [doi:. Immunological considerations for embryonic and induced pluripotent stem cell banking,. Philos Trans R SocLond B Biol Sci. 2011, 366(1575), pp. 2312–2322, doi: https://doi.org/10.1098/rstb.2011.0030 .

T.R. Nayak, H. Andersen, V.S. Makam, C. Khaw, S. Bae, X.F. Xu, P.L.R. Ee, J.H. Ahn, B.H. Hong, G. Pastorin, B. Ozyilmaz, ACS Nano, 5 (6) (2011), pp. 4. Graphene for controlled and accelerated osteogenic differentiation of human mesenchymal stem cells,. ACS Nano. 2011, pp. 4670–4678.

Lee WC, Lim C, Shi H, Tang LAL, Wang Y, Lim CT, Loh KP. Origin of enhanced stem cell growth and differentiation on graphene and graphene oxide. ACS Nano. 2011;5(9):7334–41.

Kenry LWC, Loh KP, Lim CT. When stem cells meet graphene: opportunities and challenges in regenerative medicine. Biomaterials. 2018;155:236–50.

Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, et al. Transfer of microRNAs by embryonic stem cell microvesicles. 2009. 2009, 4(3), p. https://doi.org/10.1371/journal.pone . 0004722.

Oh, Myeongsik, et al. Exosomes derived from human induced pluripotent stem cells ameliorate the aging of skin fibroblasts. Int. J. Mol. Sci. 2018, 19(6), p. 1715.

Ramirez MI. et al. Technical challenges of working with extracellular vesicles. Nanoscale. 2018;10:881–906.

Valadi H, et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007;9:654–9.

Mateescu B, et al. Obstacles and opportunities in the functional analysis of extracellular vesicle RNA—an ISEV position paper. J. Extracell. Vesicles. 2017;6(1). https://doi.org/10.1080/20013078.2017.1286095 .

Nawaz M, et al. Extracellular vesicles: evolving factors in stem cell biology. Stem Cells Int. 2016;2016:17. Article ID 1073140.

Helfrich, Y.R., Sachs, D.L. and Voorhees, J.J. Overview of skin aging and photoaging. Dermatol. Nurs. 20, pp. 177–183, https://www.ncbi.nlm.nih.gov/pubmed/18649702 .

Julia Tigges, Jean Krutmann, Ellen Fritsche, Judith Haendeler, Heiner Schaal, Jens W. Fischer, Faiza Kalfalah, Hans Reinke, Guido Reifenberger, Kai Stühler, Natascia Ventura, Sabrina Gundermann, Petra Boukamp, Fritz Boege. The hallmarks of fibroblast ageing, mechanisms of ageing and development, 138, 2014, Pages 26–44. 2014, 138, pp. 26–44, ISSN 0047–6374, https://doi.org/10.1016/j.mad.2014.03.004 .

Huh MI, Kim MS, Kim HK, et al. Effect of conditioned media collected from human amniotic fluid-derived stem cells (hAFSCs) on skin regeneration and photo-aging. Tissue Eng Regen Med. 2014;11:171 https://doi.org/10.1007/s13770-014-0412-1 .

Togel F, Hu Z, Weiss K, et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31.

Liu J, Han G, Liu H, et al. Suppression of cholangiocarcinoma cell growth by human umbilical cord mesenchymal stem cells: a possible role of Wnt and Akt signaling. PLoS One. 2013;8:e62844.

Oh M, et al. Promotive effects of human induced pluripotent stem cell-conditioned medium on the proliferation and migration of dermal fibroblasts. Biotechnol. Bioprocess Eng. 2017;22:561–8.

Chen L, Tredget EE, Wu PY, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PloS One. 2008;3:e1886.

Bae J-S, Lee S-H, Kim J-E, Choi J-Y, Park R-W, Park JY, Park H-S, Sohn Y-S, Lee D-S, Lee EB. βig-h3 supports keratinocyte adhesion, migration, and proliferation through α3β1 integrin. Biochem. Biophys. Res. Commun. 2002;294:940–8.

Zhou B-R, Xu Y, Guo S-L, Xu Y, Wang Y, Zhu F, Permatasari F, Wu D, Yin Z-Q, Luo D. The effect of conditioned media of adipose-derived stem cells on wound healing after ablative fractional carbon dioxide laser resurfacing. BioMed Res. Int. 2013;519:126.

Peng Y, Baulier E, Ke Y, Young A, Ahmedli NB, Schwartz SD, et al. Human embryonic stem cells extracellular vesicles and their effects on immortalized human retinal Müller cells. PLoS ONE. 2018, 13(3), p. https://doi.org/10.1371/journal.pone.019400 .

Harris MT, Butler DL, Boivin GP, Florer JB, Schantz EJ, Wenstrup RJ. Mesenchymal stem cells used for rabbit tendon repair can form ectopic bone and express alkaline phosphatase activity in constructs. J Orthop Res. 2004;22:998–1003.

Mascetti VL, Pedersen RA. Human-mouse chimerism validates human stem cell pluripotency. Cell Stem Cell. 2016;18:67–72.

Gandia C, Armiñan A, García-Verdugo JM, Lledó E, Ruiz A, Miñana MD, Sanchez-Torrijos J, Payá R, Mirabet V, Carbonell-Uberos F, Llop M, Montero JA, Sepúlveda P. Human dental pulp stem cells improve left ventricular function, induce angiogenesis, and reduce infarct size in rats with acute myocardial infarction. Stem Cells. 2007;26(3):638–45.

Perry BC, Zhou D, Wu X, Yang FC, Byers MA, Chu TM, Hockema JJ, Woods EJ, Goebel WS. Collection, cryopreservation, and characterization of human dental pulp-derived mesenchymal stem cells for banking and clinical use. Tissue Eng Part C Methods. 2008;14(2):149–56.

Garcia-Olmo D, Garcia-Arranz M, Herreros D, et al. A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum. 2005;48:1416–23.

de Mendonça CA, Bueno DF, Martins MT, Kerkis I, Kerkis A, Fanganiello RD, Cerruti H, Alonso N, Passos-Bueno MR. Reconstruction of large cranial defects in nonimmunosuppressed experimental design with human dental pulp stem cells. J Craniofac Surg. 2008;19(1):204–10.

Seo BM, Sonoyama W, Yamaza T, Coppe C, Kikuiri T, Akiyama K, Lee JS, Shi S. SHED repair critical-size calvarial defects in mice. Oral Dis. 2008;14(5):428–34.

Abbas, Diakonov I., Sharpe P. Neural crest origin of dental stem cells. Pan European Federation of the International Association for Dental Research (PEF IADR). 2008, Vols. Seq #96 - Oral Stem Cells.

Kerkis I, Ambrosio CE, Kerkis A, Martins DS, Gaiad TP, Morini AC, Vieira NM, Marina P, et al. Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs. J Transl Med. 2008;6:35.

Xianrui Yang, Li Li, Li Xiao, Donghui Zhang. Recycle the dental fairy’s package: overview of dental pulp stem cells. Stem Cell Res Ther . 2018, 9, 1, 1. https://doi.org/10.1186/s13287-018-1094-8 .

Wang J, Wang X, Sun Z, Wang X, Yang H, Shi S, Wang S. Stem cells from human-exfoliated deciduous teeth can differentiate into dopaminergic neuron-like cells. Stem Cells Dev. 2010;19:1375–83.

Wang J, et al. The odontogenic differentiation of human dental pulp stem cells on nanofibrous poly (L-lactic acid) scaffolds in vitro and in vivo. Acta Biomater. 2010;6(10):3856–63.

Davies OG, Cooper PR, Shelton RM, Smith AJ, Scheven BA. A comparison of the in vitro mineralisation and dentinogenic potential of mesenchymal stem cells derived from adipose tissue, bone marrow and dental pulp. J Bone Miner Metab. 2015;33:371–82.

Huang GT-J, Shagramanova K, Chan SW. Formation of odontoblast-like cells from cultured human dental pulp cells on dentin in vitro. J Endod. 2006;32:1066–73.

Shi S, Robey PG, Gronthos S. Comparison of human dental pulp and bone marrow stromal stem cells by cDNA microarray analysis. Bone. 2001;29(6):532–9.

Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97:13625–30.

Nuti N, Corallo C, Chan BMF, Ferrari M, Gerami-Naini B. Multipotent differentiation of human dental pulp stem cells: a literature review. Stem Cell Rev Rep. 2016;12:511–23.

Ferro F, et al. Dental pulp stem cells differentiation reveals new insights in Oct4A dynamics. PloS One. 2012;7(7):e41774.

Conde MCM, Chisini LA, Grazioli G, Francia A, Carvalho RVd, Alcázar JCB, Tarquinio SBC, Demarco FF. Does cryopreservation affect the biological properties of stem cells from dental tissues? A systematic review. Braz Dent J. 2016;1210(6):633-40. https://doi.org/10.1590/0103-6440201600980 .

Papaccio G, Graziano A, d’Aquino R, Graziano MF, Pirozzi G, Menditti D, De Rosa A, Carinci F, Laino G. Long-term cryopreservation of dental pulp stem cells (SBP-DPSCs) and their differentiated osteoblasts: a cell source for tissue repair. J Cell Physiol. 2006;208:319–25.

Alge DL, Zhou D, Adams LL, et. al. Donor-matched comparison of dental pulp stem cells and bone marrow-derived mesenchymal stem cells in a rat model. J Tissue Eng Regen Med. 2010;4(1):73–81.

Jo Y-Y, Lee H-J, Kook S-Y, Choung H-W, Park J-Y, Chung J-H, Choung Y-H, Kim E-S, Yang H-C, Choung P-H. Isolation and characterization of postnatal stem cells from human dental tissues. Tissue Eng. 2007;13:767–73.

Gronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, DenBesten P, Robey PG, Shi S. Stem cell properties of human dental pulp stem cells. J Dent Res. 2002;81:531–5.

Laino G, d’Aquino R, Graziano A, Lanza V, Carinci F, Naro F, Pirozzi G, Papaccio G. A new population of human adult dental pulp stem cells: a useful source of living autologous fibrous bone tissue (LAB). J Bone Miner Res. 2005;20:1394–402.

Zainal A, Shahrul H, et al. In vitro chondrogenesis transformation study of mouse dental pulp stem cells. Sci World J. 2012;2012:827149.

Wei X, et al. Expression of mineralization markers in dental pulp cells. J Endod. 2007;33(6):703–8.

Dai J, et al. The effect of co-culturing costal chondrocytes and dental pulp stem cells combined with exogenous FGF9 protein on chondrogenesis and ossification in engineered cartilage. Biomaterials. 2012;33(31):7699–711.

Vasandan AB, et al. Functional differences in mesenchymal stromal cells from human dental pulp and periodontal ligament. J Cell Mol Med. 2014;18(2):344–54.

Werle SB, et al. Carious deciduous teeth are a potential source for dental pulp stem cells. Clin Oral Investig. 2015;20:75–81.

Nemeth CL, et al. Enhanced chondrogenic differentiation of dental pulp stem cells using nanopatterned PEG-GelMA-HA hydrogels. Tissue Eng A. 2014;20(21–22):2817–29.

Paino F, Ricci G, De Rosa A, D’Aquino R, Laino L, Pirozzi G, et al. Ecto-mesenchymal stem cells from dental pulp are committed to differentiate into active melanocytes. Eur. Cell Mater. 2010;20:295–305.

Ferro F, Spelat R, Baheney CS. Dental pulp stem cell (DPSC) isolation, characterization, and differentiation. In: Kioussi C, editor. Stem cells and tissue repair. Methods in molecular biology (methods and protocols): Humana Press. 2014;1210.

Ishkitiev N, Yaegaki K, Imai T, Tanaka T, Nakahara T, Ishikawa H, Mitev V, Haapasalo M. High-purity hepatic lineage differentiated from dental pulp stem cells in serum-free medium. J Endod. 2012;38:475–80.

Download references

Acknowledgements

Not applicable.

This work is supported by Wrocław Medical University in Poland.

Availability of data and materials

Please contact author for data requests.

Author information

Authors and affiliations.

Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland

Wojciech Zakrzewski, Maria Szymonowicz & Zbigniew Rybak

Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland

Maciej Dobrzyński

You can also search for this author in PubMed   Google Scholar

Contributions

WZ is the principal author and was responsible for the first draft of the manuscript. WZ and ZR were responsible for the concept of the review. MS, MD, and ZR were responsible for revising the article and for data acquisition. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Wojciech Zakrzewski .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Cite this article.

Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. et al. Stem cells: past, present, and future. Stem Cell Res Ther 10 , 68 (2019). https://doi.org/10.1186/s13287-019-1165-5

Download citation

Published : 26 February 2019

DOI : https://doi.org/10.1186/s13287-019-1165-5

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Differentiation
• Pluripotency
• Induced pluripotent stem cell (iPSC)
• Stem cell derivation
• Growth media
• Tissue banks
• Tissue transplantation

Stem Cell Research & Therapy

ISSN: 1757-6512

• Submission enquiries: Access here and click Contact Us
• General enquiries: [email protected]

Home » 5 stem cell success stories

5 stem cell success stories

Dec 2, 2019 | Blog

Stem cell science is rapidly advancing, and more and more stem cell success stories are reported all the time. Once the stuff of science fiction, the promise of stem cells are now a life-changing reality for many people around the world.

These powerful cells have the unique ability to self-renew and develop into various different cell types that can treat a vast array of conditions.

First reported in the Daily Mail , these five stem cell success stories tell the inspiring story of people who recently received stem cell-based therapies.

Reema Sandhu, Multiple Sclerosis

Reema Sandhu’s stem cell success story started five years ago, when she was diagnosed with multiple sclerosis . The condition affects the brain and spinal cord, resulting in a wide range of life-altering symptoms such as visual impairments, muscle spasms and memory problems.

Despite receiving high dose drugs for her condition, Reema did not see any improvement and suffered from several side-effects.

After years of frustration, she decided to opt for private treatment and following a dose of chemotherapy to destroy her immune system, began to receive stem cell treatments in January.

She then received an autologous stem cell transplant, where her own stem cells were collected from her blood and returned to her body via intravenous infusion.

Significant improvements were immediately noticeable, particularly with Reema’s brain function. Two months after the transplant, her vision was restored and she returned to work.

These positive outcomes suggest that Reema’s MS has stopped progressing as a result of her stem cell transplant.

Dave Randle, Heart Attack

After suffering a heart attack in 2016, Dave Randle was left with significant heart failure and a terrifying warning from consultants: he would be dead by Christmas.

However, after discovering that stem cells could treat damaged hearts , Dave signed up for treatment at Bart’s Hospital earlier this year.

He received injections for five consecutive days that encouraged his bone marrow to release stem cells into his blood stream. These cells were then isolated and infused back into his heart.

Just weeks after the transplant, Dave’s stem cell success story had a happy ending – he began to feel better and doctors noticed substantial improvements.

George Norton, Acute Lymphoblastic Leukaemia

In 2005, George Norton was diagnosed with a form of blood cancer called Acute Lymphoblastic Leukaemia (ALL) .

After a relapse in 2014, George received a run of chemotherapy followed by a stem cell transplant from a donor through the Anthony Nolan charity, which works with leukaemia and haematopoietic stem cell transplants.

The aim of the transplant was to create a new, healthy immune system to fight the cancer and kill any leukaemia cells in the body.

Since then, George has led a healthy life free of leukaemia.

Andrew Robinson, Arthritis

47-year-old Andrew Robinson had one of the most promising stem cell success stories.

He was told that he would need a knee replacement after suffering from years of pain and swelling due to knee arthritis . However, Andrew was then recommended an alternative to knee replacement: a chondrotissue graft procedure.

This procedure involves inserting a ‘scaffold’ into the bone, which fosters the growth of new cartilage by releasing stem cells collected from the bone marrow.

Andrew was able to walk again just 10 weeks after treatment, and has now returned to his active lifestyle.

Deepan Shah, Crohn’s disease 

Having endured aggressive Crohn’s disease throughout his childhood, Deepan Shah was referred for a clinical trial investigating the use of stem cells to reset the immune system and stop its attacks on the gut.

Treatment began with chemotherapy followed by injections to encourage stem cell growth, which were then collected and infused into his body. Soon after treatment, Deepan was able to come off his medication.

Whilst Deepan still has Crohn’s disease and occasionally experiences symptoms, he is now able to lead a normal life.

These stem cell success stories demonstrate the life-changing potential of regenerative medicine in the treatment of a wide array of conditions – from arthritis to blood cancers and more. Find out more here .

• https://www.dailymail.co.uk/health/article-7674229/Patients-reveal-reaped-remarkable-benefits-stem-cells.html

Request a Welcome Pack

Find out more about cord blood banking by downloading a Welcome Pack now.

Title* - Select - Mr Mrs Miss Ms Dr Prof Sir Madam Other

Due Date Day 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Month 01 02 03 04 05 06 07 08 09 10 11 12 Year 2024 2025

Not pregnant

By post? Yes

Recent Posts

Pin It on Pinterest

Developmental Biology and Stem Cell

The Department of Genetics and Genome Sciences has a strong focus on developmental and stem cell biology.  We use a variety of cell and animal models to study the impact of genetic and epigenetic aberrations on normal development and their contribution to disease. 

The advent of embryonic and induced pluripotent stem cell technology has enabled temporal access to disease-relevant cells and tissues. Many labs throughout the department are using pluripotent stem cell technology to define the mechanisms underlying normal development and a spectrum of disorders including the labs of Tony Wynshaw-Boris (autism and microcephaly), Ann Harris (cystic fibrosis), Paul Tesar (multiple sclerosis and other myelin disorders), Ashleigh Schaffer (neurogenetic disorders), Fulai Jin (regulation of pluripotency), Helen Miranda (motor neuron disorders), Yan Li (diabetes), and Peter Scacheri (CHARGE syndrome). 

Mouse models and advancements in genome engineering such as CRISPR/Cas9 are being used to study endocrine disorders in David Buchner ’s lab, cystic fibrosis in the labs of Mitch Drumm , Craig Hodges , and Ron Conlon , social behavioral disorders in Tony Wynshaw-Boris ’ lab, and neurogenetic disorders in the labs of Ashleigh Schaffer and Paul Tesar .

The department also has a longstanding interest in germ cell biology and current efforts are focused on germline ovarian stem cell biology led by Helen Salz , spermatogenesis led by Shih-Hsing Leir and Ann Harris , and ovarian insufficiency led by David Buchner .  

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals

Stem cells articles from across Nature Portfolio

Stem cells are cells that have the capacity to self-renew by dividing and to develop into more mature, specialised cells. Stem cells can be unipotent, multipotent, pluripotent or totipotent, depending on the number of cell types to which they can give rise.

Threonine fuels brain tumor growth through a conserved tRNA modification

A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N 6 -threonylcarbamoyladenosine (t 6 A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.

Partial reprogramming of the mammalian brain

Xu and colleagues used partial OSKM reprogramming in aged mice to drive cell-type proportions of the subventricular zone to more youthful levels, which equates to qualified rejuvenation of a neurogenic niche that is defined, in part, by restoration of neuroblast levels.

• Niels C. Asmussen
• Marissa J. Schafer

Exit from totipotency is controlled by DUXBL in mice

In mice, zygotic genome activation occurs at onset of the two-cell stage in embryonic development and coincides with the exit from totipotency. Our work shows that the transcription factor DUXBL participates in silencing part of the stage-specific two-cell-associated transcriptional program and is required for development to proceed.

Related Subjects

• Adult stem cells
• Cancer stem cells
• Embryonic germ cells
• Embryonic stem cells
• Epigenetic memory
• Haematopoietic stem cells
• Heart stem cells
• Intestinal stem cells
• Mammary stem cells
• Mesenchymal stem cells
• Multipotent stem cells
• Muscle stem cells
• Neural stem cells
• Pluripotent stem cells
• Regeneration
• Reprogramming
• Self-renewal
• Skin stem cells
• Stem-cell differentiation
• Stem-cell niche
• Totipotent stem cells
• Transdifferentiation

Latest Research and Reviews

Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function

He et al. characterizes a role of microcephalin (MCPH1), a known regulator of DNA damage response, in hematopoietic stem cell (HSC) aging demonstrating nuclear MCPH1 translocation that leads to activation of necroptosis and deterioration of HSC function with age.

• Yuqian Wang
• Jianwei Wang

Reprogramming fibroblast into human iBlastoids

A protocol for the generation of induced blastoids, an in vitro integrated model of the human blastocyst derived via somatic reprogramming. This model overcomes restrictions associated with the use of human blastocysts in embryology research.

• Jia Ping Tan
• Xiaodong Liu
• Jose M. Polo

Exosomes derived from mesenchymal stem cells in diabetes and diabetic complications

• Yu-Rui Jiao
• Kai-Xuan Chen
• Chang-Jun Li

SARS-CoV-2 infection activates inflammatory macrophages in vascular immune organoids

• Chiu Wang Chau
• Ryohichi Sugimura

Tailored apoptotic vesicles promote bone regeneration by releasing the osteoinductive brake

• Yawen Cheng
• Yunsong Liu

Therapeutic role of PTEN in tissue regeneration for management of neurological disorders: stem cell behaviors to an in-depth review

• Ruishuang Ma

News and Comment

A map of mouse embryogenesis.

• Madhura Mukhopadhyay

A developmental exit from totipotency

A paper in Nature Genetics identifies a mechanism involving the transcription factor DUXBL that controls the development of early embryonic mouse cells past stages marked by totipotency.

‘Mini liver’ will grow in person’s own lymph node in bold new trial

Biotechnology firm LyGenesis has injected donor cells into a person with liver failure for the first time.

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Stem Cell Reports
• v.16(7); 2021 Jul 13

Recognizing the ethical implications of stem cell research: A call for broadening the scope

Lars s. assen.

1 Julius Center for Health Sciences and Primary Care, Department of Medical Humanities, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands

Karin R. Jongsma

Rosario isasi.

2 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 3310, USA

Marianna A. Tryfonidou

3 Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CM Utrecht, the Netherlands

Annelien L. Bredenoord

The ethical implications of stem cell research are often described in terms of risks, side effects, safety, and therapeutic value, which are examples of so-called hard impacts. Hard impacts are typically measurable and quantifiable. To understand the broader spectrum of ethical implications of stem cell research on science and society, it is equally important to recognize soft impacts. Soft impacts are the effects on behavior, experiences, actions, moral values, and social structures; these are often indirect effects of stem cell research. The combined notions of hard and soft impacts offer a broader way of thinking about the social and ethical implications of stem cell research and can help to steer stem cell research into a sociable desirable direction. Soft impacts enable researchers to become more aware of the broad range of significant implications involved in their work and deserve equal attention for understanding such ethical and societal effects of stem cell research.

The ethical implications of stem cell research are often discussed in terms of risks, side effects, and safety, which are examples of hard impacts. In this article, Assen and colleagues argue that to understand the broader spectrum of ethical implications of stem cell research on science and society, it is important to recognize the so-called soft impacts.

Introduction

Stem cell science has expanded in the past two decades. These new research possibilities raise ethical and policy questions. While ethical reflections on embryonic stem cells have strongly focused on the moral status of the embryo, this is not the case with induced pluripotent stem cells (iPSCs) and adult stem cells. Ethical reflections surrounding these types of stem cells focus primarily on risks of stem cell interventions, what kind of harm unproven stem cell interventions could cause, how to seek informed consent of patients, and questions about ownership ( Andrews et al., 2015 ; Hyun, 2010 ; King and Perrin, 2014 ; MacPherson and Kimmelman, 2019 ). However, stem cell research has other important ethical implications that are easily overlooked.

For example, between 2013 and 2014, clinical researchers conducted a first-in-human study with a mix of allogeneic mesenchymal stem cells and autologous chondrons as an intervention for stimulating autologous cartilage repair in the knee, with promising results ( de Windt et al., 2017 ). During the clinical trial, there were drawbacks in the recovery of some participants. They did not adhere to the instructions of the researchers to be careful with burdening their knee too much, which inadvertently negatively influenced their rehabilitation process. Possibly, some of the patients believed that the stem cell intervention was more effective than it really was. The drawback was not a direct effect of the stem cell intervention itself. It was an effect of how the stem cell intervention affected patient’s beliefs about the therapeutic value that resulted in an undesirable and unforeseen effect of this intervention. Such a mistaken belief in which the research participant overestimates the benefits of the intervention is often referred to as therapeutic misestimation ( Habets et al., 2016 ; Horng and Grady, 2003 ). This belief can have several causes; it could, for example, have been a result of the positive portrayal of stem cell research in the media ( Caulfield et al., 2016 ). The researchers of the aforementioned study adhered to ethical guidelines, including approval by the Dutch Central Committee on Research Involving Human Subjects, proper informed consent procedures, and taking preventive measures to minimize or mitigate possible harm ( de Windt et al., 2017 ). Despite good preparations and preventive measures, the drawback in recovery was undesirable and, in hindsight, to some extent avoidable. In subsequent studies, researchers and physical therapists used the described example to stress to patients the importance of being careful with mobilizing their knee after surgery.

This example indicates that the existing narrow view of ethical considerations fails to do justice to all ethical implications related to the use and integration of stem cells in society. This view focuses primarily upon issues, such as the harm of unproven stem cell interventions, and side effects, such as teratoma formation, storage of donated tissue, and discussions about ownership ( Andrews et al., 2015 ; Hyun, 2010 ; King and Perrin, 2014 ; MacPherson and Kimmelman, 2019 ). Stem cell research could benefit from a broader conception of ethical considerations, which could contribute to developing effective strategies to enhance the benefits of stem cells and mitigate undesirable effects. This broader conception of ethical implications can be promoted by distinguishing between the narrow view as “hard impacts,” and a type of ethical considerations that is now often being overlooked, referred to as “soft impacts” ( Swierstra, 2015 ; Swierstra and te Molder, 2012 ; van der Burg, 2009 ). The terms hard and soft do not refer to the severity of the impact, but to what is actually impacted.

Hard impacts are characterized by two aspects ( Swierstra, 2015 ). First, there is a causal physical relationship between the research, intervention, or technology, and the effect it has. For example, how a drug (technology) improves the health (the effect), or how a drug leads to an undesirable side effect. Second, the research or technology outcome is quantifiable and measurable, such as the gravity of an immune response, the type of gene-expression pattern of stem cell lines ( Scudellari, 2016 ), and the costs to clinically translate stem cell research ( Neofytou et al., 2015 ). These outcomes could, for instance, indicate an increase or decrease in harm. In other words, hard impacts are direct (physical) outcomes or financial effects of the research, technology, or intervention. It often includes risks, side effects, costs, safety, and therapeutic value. These impacts can be both positive and negative for individuals and society.

Soft impacts are characterized by how technologies, research, or interventions affect experiences, perceptions, actions, social structures, and/or moral values, and are therefore not easily quantifiable or measurable ( van der Burg, 2009 ). In that respect soft impacts are often about the psychological and social effects of research and technology. Compared with hard impacts, soft impacts are outcomes that are an indirect effect of research or technology. An overview of potential hard and soft impacts can be found in Table 1 .

Potential hard and soft impacts of stem cell research and stem cell-based interventions

This paper argues that the notion of soft impacts could help stem cell researchers to become more aware of the wider array of ethical implications involved in their work. The combined notions of hard and soft impacts offer a broader way of thinking about the ethical implications of stem cell research and can help to steer stem cell research and innovation into a desirable direction. Therefore, these terms will be used in this paper as a heuristic tool to exemplify the different ways of thinking about ethical implications of stem cell research and interventions. Taking both types of impacts into account could have merits for responsible development, use, and policy of stem cell interventions.

Hard and soft impacts: Examples

To illustrate the difference of hard and soft impacts of stem cell research, we draw on organoid research as an example and its impacts on personalized medicine, costs, and animal research. An organoid is defined as an in-vitro -generated stem cell-derived structure, mimicking the architecture and physiology of intact organs. These organoids can, among others, be derived from iPSCs and adult stem cells and it has been proven to be a suitable model for disease-modeling research ( Bredenoord et al., 2017 ; de Souza, 2018 ).

A positive hard impact of this type of technology is that it allows for the creation of new types of personalized interventions, with an increased therapeutic value compared with non-personalized interventions, thereby reducing harm. In terms of quality adjusted life years (QALYs), personalized interventions could be cost-effective ( Hatz et al., 2014 ). However, since personalized medicine may lead to an increase in QALYs compared with conventional alternatives, it is likely that overall costs will also increase ( Tiriveedhi, 2018 ). Therefore, the development of organoids for personalized interventions may also increase the overall costs for healthcare. This financial harm is a possible negative hard impact of the success side of this technology.

By focusing merely on the increasing costs of medical research and innovations, one may overlook the soft impacts and how technological developments are embedded in a broader social context. Within this context, organoid research used in personalized medicine could potentially affect the financial sustainability of solidarity-based healthcare systems. An example of solidarity in healthcare is the collective responsibility for paying the costs in healthcare ( Ter Meulen and Maarse, 2008 ). Here, the insured population contributes with a relatively small amount of money that is reserved for paying the total or a (large) part of society's healthcare costs. When organoid research-based innovations indeed lead to considerably increased healthcare costs, it could affect the surrounding system of solidarity and consequentially our attitudes to others.

The differences between hard and soft impacts are as well highlighted in the example of how organoid technology affects animal research. A possible hard impact of organoid research is reduction and/or replacement of animal studies, two of the 3Rs principles (refinement, reduction, and replacement) that contribute to ethical research ( Bredenoord et al., 2017 ). Animal studies have been considered necessary and acceptable—even if controversial—for conducting safety and efficacy studies. Within this context, a conceivable soft impact of organoid technology is that it could affect how animal studies are perceived . Taking the 3Rs of animal studies in mind as an ethical ground rule, it is possible that the ethical acceptability of certain animal studies will be assessed differently because of the possibility to test efficacy and safety by means of organoids. Two concepts are relevant here: subsidiarity and proportionality ( Jans et al., 2018 ). Subsidiarity implies that an action is acceptable because that action is the least morally problematic way of performing research. In that light, organoid technology is generally considered less morally problematic than research on experimental animals. Also, the proportionality of animal research is relevant to consider. This refers to the question whether animal research for testing the effectiveness and safety of new therapies is still proportional ( Jans et al., 2018 ). In the past, studies in which harm was inflicted on animals were considered proportional for acquiring insights into the safety and efficacy of interventions. Nowadays, with organoid technology, animal testing could in certain cases be perceived as disproportional, since it may not be necessary to inflict harm on animals for acquiring insights in efficacy and safety. Therefore, the existence of organoid technology can affect the permissibility of using certain animal studies. Important to note is that, while the field is evolving toward animal-free substitutes, organoid studies are often also not completely “animal-free.” This is due to the fact that Matrigel, which is commonly used to provide the cells with a 3D environment in which they can thrive, is derived from mice ( Bredenoord et al., 2017 ).

By considering hard impacts of a technology or intervention we find multiple advantages. Quantifying outcomes and the assessment of directs risks help to develop safety measures to prevent harm to the health and well-being of patients and research participants. Furthermore, it helps to create a picture of the financial costs. However, quantifying diseases, cells, side effects, and costs, is only part of the ethical implications of these interventions, as the above-mentioned examples explicate. A narrow focus on hard impacts alone comes with the risk of ignoring aspects that are important for the success and acceptance of these interventions. The effect of technology co-producing our morality, such as solidarity and the perception of animal research, is often referred to as “techno-moral change” ( Swierstra, 2015 ). Insights into this techno-moral change through considering soft impacts could contribute to dealing with the ethical challenges of stem cell research. Being oblivious to the soft impacts of technologies and interventions means that the personal and societal effects are missed.

Implications for stem cell research(ers)

Becoming aware of the soft impacts of stem cell research could help researchers to anticipate ethical implications and to develop new skills. As a result, researchers could benefit from soft impacts to positively impact the quality of research; it provides a way of anticipating and understanding the ethical implications of stem cell technologies.

Funding agencies focus increasingly on the social value of research, thereby making it more relevant for researchers to contemplate social value and impact. Soft impacts can help to analyze the social value of research. Focusing on soft impacts enables to not only look at treatment effects on a disease or saving money, but also how the research could potentially improve societal structures and increase social justice. For example, the social value of stem cell research could be that it promotes social justice or helps to empower a group of patients (e.g., destigmatize or physically benefit and enable more participation in society) and helps the target group to flourish.

To better anticipate the ethical dimensions of stem cell research and stem cell-based interventions, we need scientists who recognize both hard and soft impacts. To this end, training or educating in terms of hard and soft impacts could be a tool for recognizing the ethical implications of stem cell research and a step toward contemplating whether to mitigate, prevent, or stimulate certain soft impacts. This could, for instance, be done by creating or implementing courses in biomedical curricula that involve how early patient involvement could be achieved, how the public could be engaged, and what the ethics of biomedical research involve. To prevent that these courses reinforce the focus on hard impacts, ethical training or education should be broadened by reflecting upon how stem cell research affects experiences, perceptions, actions, social structures, and moral values.

Patients can offer valuable insights into how stem cell research could affect perceptions, expectations, and actions. Engaging with patients could give insights into how their disease creates specific drawbacks and expectations. Doing this in an early stage of the research, could aid researchers in preventing the negative and foster the positive impacts in a timely manner ( Supple et al., 2015 ). Courses should address under which conditions early patient involvement is fruitful, how and when this could be implemented in the study design, and which skills are needed to have meaningful interactions with patients.

Similarly, public engagement and science communication could be addressed in curricula or workshops. Ideally, this should lead to interactions and dialogue where there is room for the concerns of the public ( Reincke et al., 2020 ). Such interactions could provide information about possible social and societal implications of stem cell research. Courses should focus upon how such dialogue could be organized and on skills that foster dialogue and lay translation of research.

Furthermore, education about the ethics of biomedical research can stimulate moral awareness by researchers. Using not only factual information but also vignettes and moral scenarios ( Swierstra, 2015 ) can offer insights in how stem cell research could affect social practices, moral values, or social structures. Other possible enabling methods are organizing interventions within research teams and using games and roleplay. These could be embedded in PhD programs and conference workshops. Altogether, these types of activities may promote the moral imagination ( Coeckelbergh, 2006 ) of researchers and students and thereby help them to learn to think about the soft impacts of their work. By doing so, moral imagination could help to understand and anticipate techno-moral change: the way that technology and morality co-shape each other ( Swierstra, 2015 ). It should be noted that educational research about the desired content and design is necessary.

Moreover, the notion of hard and soft impacts establishes a vocabulary and a broader way of looking at and reflecting on implications of stem cell technology. These insights could serve as a starting point for discussions about responsible and desirable stem cell science and what would be needed to create these circumstances.

Implications for policy and regulation

Regulation clusters a broad range of rules or principles governing and evaluating human behavior, thereby establishing boundaries between what should be considered acceptable or indefensible actions. As regulation is influenced by local historical, socio-cultural, political, and economic factors, assessing the hard and soft impacts in both policy debates and outcomes contributes to the development of robust regulation. By doing so, regulation not only reflects society’s shared moral values, but also truly takes into account the broad range of impacts for individuals, communities, and societies. Thus, focusing solely on hard impacts is too narrow, as other important factors for the responsible development and use of stem cell interventions can be overlooked.

To advance responsible development of stem cell interventions, an important question is whether new rules and legislation for promoting ethically sound research should be implemented or how much leeway organizations and researchers should have to deal with the impacts themselves. Rules and regulation might be helpful for conceptualizing and adherence to responsibilities ( Coeckelbergh, 2006 ). For instance, the ISSCR (International Society for Stem Cell Research) provides guidelines for safety and efficacy studies, and guidelines for the derivation, banking, and distribution of stem cell lines. This already helps to prevent and mitigate certain hard impacts of stem cell research, such as loss of reliable data due to contamination of stem cell lines and privacy issues in biobanking ( International Society for Stem Cell Research (ISSCR), 2016 ). As such, guidelines, rules, and regulations help to allocate accountability for processes or operations to researchers or groups of researchers and establish international standards. However, this approach has its limitations, since guidelines, rules, and regulations tend to focus on moral impacts that are measurable or quantifiable. When soft impacts are framed in guidelines, rules, and regulations, we risk that possible socio-ethical challenges might be overlooked. Therefore, guidelines, rules, and regulations cannot and should not do all the moral work. It is important to articulate and explicate the ethical dimensions in stem cell research, where it could help researchers to make better decisions about how the research could be conducted in a desirable and responsible manner. The latter in turn, could ultimately be translated in improved policies or regulations.

Concluding remarks

So far, academic literature, policy, and researchers have focused primarily on hard impacts of stem cell research. Ethical reflection on stem cell research and technology could be broadened by focusing on soft impacts as well. While the term “soft” may sound misleading as being insignificant, the soft impacts are influential for the use and acceptance of these technologies and require more academic and regulatory attention. Broadening the scope of ethical reflection has implications for education, policy, and regulation. The challenge is to find a balance between how much freedom and education researchers should have to deal with possible ethical implications themselves and where policy and regulation could be of help.

It should be noted that, while hard and soft impacts are meaningful heuristic tools to broaden the scope of ethical implications one could assess, the distinction between hard and soft impacts is primarily an analytical distinction, and not always crystal clear ( Swierstra, 2015 ). For instance, certain soft impacts could become hard impacts over time. Nonetheless, anticipating both hard and soft impacts could steer research and innovation into a desirable direction.

More importantly, having a more comprehensive understanding of the ethical implications of stem cell research could help researchers and others to think about how to anticipate and thereby possibly prevent or mitigate possible future challenges instead of dealing with ethical challenges once they emerge.

Acknowledgments

This project has received funding from the European Union's Horizon 2020 research and innovation program iPSpine under grant agreement no. 825925. M.A.T. receives funding from the Dutch Arthritis Society (LLP22). We thank Roel Custers and Lucienne Vonk for sharing their experiences with us and we would like to thank our colleagues at the UMCU for commenting on early draft versions of the paper. Moreover, we thank the anonymous reviewers for their constructive feedback.

Author contributions

L.S.A., K.R.J., and A.L.B. conducted the initial desk research and prepared the first draft of the manuscript. M.A.T. and R.I. commented on and contributed to several draft versions. L.S.A. prepared the final manuscript for submission. All authors approve of the final version.

Conflicts of interests

M.A.T. is a member of the scientific advisory board of JOR Spine board and a scientific advisor for CentryX.

A.L.B. is a member of IQVIA's Ethics Advisory Panel. A.L.B. and R.I. are members of the Ethics Committee of ISSCR.

• Andrews P.W., Baker D., Benvinisty N., Miranda B., Bruce K., Brüstle O., Choi M., Choi Y.-M., Crook J.M., de Sousa P.A. Points to consider in the development of seed stocks of pluripotent stem cells for clinical applications: international stem cell banking initiative (ISCBI) Regen. Med. 2015; 10 :1–44. [ PubMed ] [ Google Scholar ]
• Bredenoord A.L., Clevers H., Knoblich J.A. Human tissues in a dish: the research and ethical implications of organoid technology. Science. 2017; 355 doi: 10.1126/science.aaf9414. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• van der Burg S. Taking the “soft impacts” of technology into account: broadening the discourse in research practice. Soc. Epistemol. 2009; 23 :301–316. [ Google Scholar ]
• Caulfield T., Sipp D., Murry C.E., Daley G.Q., Kimmelman J. Confronting stem cell hype. Science. 2016; 352 :776–777. [ PubMed ] [ Google Scholar ]
• Coeckelbergh M. Regulation or responsibility? Autonomy, moral imagination, and engineering. Sci. Technol. Hum. Values. 2006; 31 :237–260. [ Google Scholar ]
• Habets M.G., van Delden J.J., Bredenoord A.L. Studying the lay of the land: views and experiences of professionals in the translational pluripotent stem cell field. Regen. Med. 2016; 11 :63–71. [ PubMed ] [ Google Scholar ]
• Hatz M.H., Schremser K., Rogowski W.H. Is individualized medicine more cost-effective? A systematic review. Pharmacoeconomics. 2014; 32 :443–455. [ PubMed ] [ Google Scholar ]
• Horng S., Grady C. Misunderstanding in clinical research: distinguishing therapeutic misconception, therapeutic misestimation, and therapeutic optimism. IRB: Ethics Hum. Res. 2003; 25 :11–16. [ PubMed ] [ Google Scholar ]
• Hyun I. The bioethics of stem cell research and therapy. J. Clin. Invest. 2010; 120 :71–75. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• International Society for Stem Cell Research (ISSCR) Guidelines for stem cell research and clinical translation. 2016. http://www.isscr.org/guidelines2016
• Jans V., Dondorp W., Goossens E., Mertes H., Pennings G., de Wert G. Balancing animal welfare and assisted reproduction: ethics of preclinical animal research for testing new reproductive technologies. Med. Health Care Philos. 2018; 21 :537–545. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• King N.M., Perrin J. Ethical issues in stem cell research and therapy. Stem Cell Res. Ther. 2014; 5 :85. doi: 10.1186/scrt474. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• MacPherson A., Kimmelman J. Ethical development of stem-cell-based interventions. Nat. Med. 2019; 25 :1037–1044. [ PubMed ] [ Google Scholar ]
• Ter Meulen R., Maarse H. Increasing individual responsibility in Dutch health care: is solidarity losing ground? J. Med. Philos. 2008; 33 :262–279. [ PubMed ] [ Google Scholar ]
• Neofytou E., O’Brien C.G., Couture L.A., Wu J.C. Hurdles to clinical translation of human induced pluripotent stem cells. J. Clin. Invest. 2015; 125 :2551–2557. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Reincke C.M., Bredenoord A.L., van Mil M.H. From deficit to dialogue in science communication: the dialogue communication model requires additional roles from scientists. EMBO Rep. 2020; 21 doi: 10.15252/embr.202051278. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Scudellari M. How iPS cells changed the world. Nat. News. 2016; 534 :310. doi: 10.1038/534310a. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• de Souza N. Organoids. Nat. Methods. 2018; 15 :23. [ Google Scholar ]
• Supple D., Roberts A., Hudson V., Masefield S., Fitch N., Rahmen M., de Boer W., Powell P., Wagers S. From tokenism to meaningful engagement: best practices in patient involvement in an EU project. Res. Involv. Engage. 2015; 1 :1–9. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Swierstra T. Identifying the normative challenges posed by technology’s ‘soft’ impacts. Etikk i praksis. 2015; 9 :5–20. [ Google Scholar ]
• Swierstra T., te Molder H. Risk and soft impacts. In: Roeser S., Hillerbrand R., Sandin P., Peterson M., editors. Handbook of Risk Theory. Springer; 2012. pp. 1049–1066. [ Google Scholar ]
• Tiriveedhi V. Impact of precision medicine on drug repositioning and pricing: a too small to thrive crisis. J. Pers. Med. 2018; 8 :36. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• de Windt T.S., Vonk L.A., Slaper-Cortenbach I.C., van den Broek M.P., Nizak R., van Rijen M.H., de Weger R.A., Dhert W.J.A., Saris D.B. Allogeneic mesenchymal stem cells stimulate cartilage regeneration and are safe for single-stage cartilage repair in humans upon mixture with recycled autologous chondrons. Stem Cells. 2017; 35 :256–264. [ PubMed ] [ Google Scholar ]