The potential of induced pluripotent stem cells (iPSCs) for modeling and treating metabolic associated fatty liver disease (MAFLD) and metabolic associated steatohepatitis (MASH) is emerging. MAFLD is a growing global health concern, currently with limited treatment options. While primary mesenchymal stem cells hold promise, iPSCs offer a versatile alternative due to their ability to differentiate into various cell types, including iPSC-derived mesenchymal stem cells. However, challenges remain, including optimizing differentiation protocols, ensuring cell safety, and addressing potential tumorigenicity risks. In addition, iPSCs offer the possibility to generate complex cellular models, including three-dimensional organoid models, which are closer representations of the human disease than animal models. Those models would also be valuable for drug discovery and personalized medicine approaches. Overall, iPSCs and their derivatives offer new perspectives for advancing MAFLD/MASH research and developing novel therapeutic strategies. Further research is needed to overcome current limitations and translate this potential into effective clinical applications.

• Metabolic associated fatty liver disease
• Metabolic associated steatohepatitis
• Nonalcoholic fatty liver disease
• Nonalcoholic steatohepatitis
• Mesenchymal stem cells
• Induced pluripotent stem cells
• In vitro liver models

• alveolar type 2 epithelial cells (AT2s)
• fibrosing interstitial lung diseases (FILDs)
• fibrotic hypersensitivity pneumonitis (fHP)
• idiopathic pulmonary fibrosis (IPF)
• induced pluripotent stem cells (iPSCs)
• lung progenitor cells
• mesenchymal stem cells (MSCs)
• stem cells

• Humans
• Induced Pluripotent Stem Cells/cytology
• Lung Diseases, Interstitial/therapy
• Lung Diseases, Interstitial/pathology
• Cell- and Tissue-Based Therapy/methods
• Animals
• Idiopathic Pulmonary Fibrosis/therapy
• Idiopathic Pulmonary Fibrosis/pathology

• KAKENHI Grant (19K17644) Japan Society for the Promotion of Science
• GSK Japan Research Grant 2021 (AS2021A000200866) GlaxoSmithKline (Japan)
• Investigator-Initiated Research Grant awarded (No. 2023-04) Dokkyo Medical University
• The Japanese Respiratory Society Boehringer Ingelheim research program (grant number none, 2023) The Japanese Respiratory Society

• GMP manufacturing
• HLA matching
• Haplobank
• Induced pluripotent stem cells
• Regenerative medicine

• Humans
• Induced Pluripotent Stem Cells/metabolism
• HLA-DRB1 Chains/metabolism
• HLA Antigens/metabolism
• HLA-B Antigens/metabolism
• HLA-A Antigens/metabolism

• Retos project iPS-PANIA Ministerio de Ciencia e Innovación
• grant no. RTC-2017-6000-1 Ministerio de Ciencia e Innovación
• PID2021-123925OB-100 Ministerio de Ciencia e Innovación
• PT20/00171 Instituto de Salud Carlos III
• 2021-SGR-00974 Agència de Gestió d'Ajuts Universitaris i de Recerca

• cartilage organoids
• disease model
• organoids
• osteoarthritis
• regeneration and repair

• assisted reproductive technology
• biobanking
• biodiversity
• conservation
• cryopreservation

• Animals
• Biodiversity
• Biological Specimen Banks
• Conservation of Natural Resources
• Endangered Species
• Humans
• Male
• Mammals
• Reproductive Techniques, Assisted

• NG2 glia
• NeuroD1
• Sox2
• astrocyte
• microRNA
• neuronal relay
• neuronal reprogramming
• pericyte
• reactive gliosis
• spinal cord injury

Induced pluripotent stem cells (iPSCs) can be produced from various somatic cells and have the ability to differentiate into various cells and tissues of the body. Regenerative medicine using iPSCs is expected to manage diseases lacking effective treatments at present. We are establishing a safe and effective iPSC stock that can be used for regenerative medicine. Our iPSC stock is recruited from healthy, consenting HLA-type homozygous donors and is made with peripheral blood-derived mononuclear cells or umbilical cord blood. We hope to minimize the influence of immune rejection by preparing HLA homozygous iPSCs. Our stock is made at the Cell Processing Center (CPC), Center for iPS Cell Research and Application (CiRA). We are preparing iPS cells that maximize matching of the Japanese population at the major HLA loci. This iPSC stock is intended to be offered not only to Japanese centers but also overseas medical institutions and companies. In August 2015, we began offering the iPSC stock for regenerative medicine and now offer 21 clones made from 5 donors.

• Clinical-grade
• HLA
• Regenerative medicine
• Stock
• iPS cells

How did the field of stem cell research develop in the years following the derivation of the first human embryonic stem cell (hESC) line?

Supported by the increasing number of clinical trials to date, significant technological advances in the past two decades have brought us ever closer to clinical therapies derived from pluripotent cells.

Since their discovery 20 years ago, the use of human pluripotent stem cells has progressed tremendously from bench to bedside. Here, we provide a concise review of the main keystones of this journey and focus on ongoing clinical trials, while indicating the most relevant future research directions.

This is a historical narrative, including relevant publications in the field of pluripotent stem cells (PSC) derivation and differentiation, recounted both through scholarly research of published evidence and interviews of six pioneers who participated in some of the most relevant discoveries in the field.

The authors all contributed by researching the literature and agreed upon body of works. Portions of the interviews of the field pioneers have been integrated into the review and have also been included in full for advanced reader interest.

The stem cell field is ever expanding. We find that in the 20 years since the derivation of the first hESC lines, several relevant developments have shaped the pluripotent cell field, from the discovery of different states of pluripotency, the derivation of induced PSC, the refinement of differentiation protocols with several clinical trials underway, as well as the recent development of organoids. The challenge for the years to come will be to validate and refine PSCs for clinical use, from the production of highly defined cell populations in clinical grade conditions to the possibility of creating replacement organoids for functional, if not anatomical, function restoration.

This is a non-systematic review of current literature. Some references may have escaped the experts’ analysis due to the exceedingly diverse nature of the field. As the field of regenerative medicine is rapidly advancing, some of the most recent developments may have not been captured entirely.

The multi-disciplinary nature and tremendous potential of the stem cell field has important implications for basic as well as translational research. Recounting these activities will serve to provide an in-depth overview of the field, fostering a further understanding of human stem cell and developmental biology. The comprehensive overview of clinical trials and expert opinions included in this narrative may serve as a valuable scientific resource, supporting future efforts in translational approaches.

ESHRE provided funding for the authors’ on-site meeting and discussion during the preparation of this manuscript. S.M.C.S.L. is funded by the European Research Council Consolidator (ERC-CoG-725722-OVOGROWTH). M.P. is supported by the Special Research Fund, Bijzonder Onderzoeksfonds (BOF01D08114). M.G. is supported by the Methusalem grant of Vrije Universiteit Brussel, in the name of Prof. Karen Sermon and by Innovation by Science and Technology in Flanders (IWT, Project Number: 150042). A.V. and B.A. are supported by the Plataforma de Proteomica, Genotipado y Líneas Celulares (PT1770019/0015) (PRB3), Instituto de Salud Carlos III. Research grant to B.H. by the Research Foundation—Flanders (FWO) (FWO.KAN.2016.0005.01 and FWO.Project G051516N). There are no conflicts of interest to declare.

Not applicable.

ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

• clinical trials
• differentiation
• human embryonic stem cell (hESC)
• human-induced pluripotent stem cells (hiPSC)
• pluripotency
• regenerative medicine

• Imaging mass spectrometry
• Induced pluripotent stem cells
• LC-MS
• Lipids
• Quality control
• Regenerative medicine

• bioactive molecules
• clinical application
• pulp regeneration
• stem cells

• Animals
• Dental Pulp/cytology
• Dental Pulp/physiology
• Humans
• Regeneration
• Stem Cells/cytology
• Stem Cells/physiology
• Tissue Engineering/methods
• Tooth, Nonvital/therapy

Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.

Resolving the immunogenicity of cells derived from induced pluripotent stem cells (iPSCs) remains an important challenge for cell transplant strategies that use banked allogeneic cells. Thus, we evaluated the immunogenicity of mouse fetal neural stem/progenitor cells (fetus-NSPCs) and iPSC-derived neural stem/progenitor cells (iPSC-NSPCs) both in vitro and in vivo. Flow cytometry revealed the low expression of immunological surface antigens, and these cells survived in all mice when transplanted syngeneically into subcutaneous tissue and the spinal cord. In contrast, an allogeneic transplantation into subcutaneous tissue was rejected in all mice, and allogeneic cells transplanted into intact and injured spinal cords survived for 3 months in approximately 20% of mice. In addition, cell survival was increased after co-treatment with an immunosuppressive agent. Thus, the immunogenicity and post-transplantation immunological dynamics of iPSC-NSPCs resemble those of fetus-NSPCs.

• Innate immunity
• Nuclear reprogramming
• Transdifferentiation

Donor-specific induced pluripotent stem cells (iPSCs) offer opportunities for personalized cell replacement therapeutic approaches due to their unlimited self-renewal potential and ability to differentiate into different somatic cells. A significant progress has been made toward generating iPSC lines that are free of integrating viral vectors, development of xeno-free culture conditions, and differentiation of pluripotent stem cells (PSCs) into functional somatic cell lineages. Since donor-specific iPSC lines are genetically identical to the individual, they are expected to be immunologically matched and these iPSC lines and their cellular derivatives are not expected to be immunologically rejected. However, studies in mouse models, utilizing rejection of teratomas as a model, have claimed that syngenic iPSC lines, especially the iPSC lines derived with integrating viral vectors, could be inherently immunogenic. This manuscript reviews current understanding of inherent immunogenicity of PSC lines, especially that of the human iPSC lines and their cellular derivatives, and strategies to overcome it.

• cell replacement therapy
• dendritic cells
• human pluripotent stem cells
• immunogenicity
• induced pluripotent stem cells

• Degenerative retinal diseases
• Macular degeneration
• Regenerative medicine
• Retina pigment epithelial cells
• Retinal development
• Stem cell

• Animals
• Clinical Trials as Topic
• Humans
• Models, Biological
• Retina/embryology
• Retina/pathology
• Retinal Degeneration/immunology
• Retinal Degeneration/therapy
• Stem Cell Transplantation

• R01 EY022079 NEI NIH HHS
• New York State Empire Stem Cell Fund
• National Eye Institute
• Macula Vision Research Foundation
• Neural Stem Cell Institute Regenerative Research Foundation

Stem cell treatments are a desirable therapeutic option to regenerate myocardium and improve cardiac function after myocardial infarction. Several different types of cells have been explored, each with their own benefits and limitations. Induced pluripotent stem cells possess an embryonic-like state and therefore have a high proliferative capacity, but they also pose a risk of teratoma formation. Mesenchymal stem cells have been investigated from both bone marrow and adipose tissue. Their immunomodulatory characteristics may permit the use of allogeneic cells as universal donor cells in the future. Lastly, studies have consistently shown that cardiac stem cells are better able to express markers of cardiogenesis compared to other cell types, as well improve cardiac function. The ideal source of stem cells depends on multiple factors such as the ease of extraction/isolation, effectiveness of engraftment, ability to differentiate into cardiac lineages and effect on cardiac function. Although multiple studies highlight the benefits and limitations of each cell type and reinforce the successful potential use of these cells to regenerate damaged myocardium, more studies are needed to directly compare cells from various sources. It is interesting to note that research using stem cell therapies is also expanding to treat other cardiovascular diseases including non-ischemic cardiomyopathies.

• Adipose tissue
• Bone marrow
• Cardiac stem cells
• Induced pluripotent stem cells
• Mesenchymal stem cells
• Myocardial infarction
• Stem cell therapy

• cancer
• epigenetics
• induced pluripotent stem cells
• regenerative medicine
• reprogramming

This research was conducted to clarify the capability of human umbilical mesenchymal stem cells conditioned medium (HU-MSCM) to promote regenerations of primary wound healing on the incision skin injury.

In this study, two approaches in vitro and in vivo already done. On in vitro analysis, tube formation was performed using HU vein endothelial cells in the presence of HU-MSCM, in some experiments cells line was incubated prior the presence of lipopolysaccharide and HU-MSCM then apoptosis assay was performed. Furthermore, in vivo experiments 12 female rats (Rattus norvegicus) were used after rats anesthetized, 7 mm wound was made by incision on the left side of the body. The wound was treated with HU-MSCM containing cream, povidone iodine was run as a control. Wound healing regenerations on the skin samples were visualized by hematoxylin-eosin staining.

In vitro models elucidate HU-MSCM may decreasing inflammation at the beginning of wound healing, promote cell migration and angiogenesis. In addition in vivo models show that the incision length on the skin is decreasing and more smaller, HE staining describe decreasing of inflammation phase, increasing of angiogenesis, accelerate fibroplasia, and maturation phase.

Taken together our observation indicates that HU-MSCM could promote the acceleration of skin tissue regenerations in primary wound healing process.

• human umbilical mesenchymal stem cells conditioned medium
• regenerations
• wound healing

Mesenchymal stem cells (MSCs) are being assessed for ameliorating the severity of graft‐versus‐host disease, autoimmune conditions, musculoskeletal injuries and cardiovascular diseases. While most of these clinical therapeutic applications require substantial cell quantities, the number of MSCs that can be obtained initially from a single donor remains limited. The utility of MSCs derived from human‐induced pluripotent stem cells (hiPSCs) has been shown in recent pre‐clinical studies. Since adult MSCs have limited capability regarding proliferation, the quantum of bioactive factor secretion and immunomodulation ability may be constrained. Hence, the alternate source of MSCs is being considered to replace the commonly used adult tissue‐derived MSCs. The MSCs have been obtained from various adult and foetal tissues. The hiPSC‐derived MSCs (iMSCs) are transpiring as an attractive source of MSCs because during reprogramming process, cells undergo rejuvination, exhibiting better cellular vitality such as survival, proliferation and differentiations potentials. The autologous iMSCs could be considered as an inexhaustible source of MSCs that could be used to meet the unmet clinical needs. Human‐induced PSC‐derived MSCs are reported to be superior when compared to the adult MSCs regarding cell proliferation, immunomodulation, cytokines profiles, microenvironment modulating exosomes and bioactive paracrine factors secretion. Strategies such as derivation and propagation of iMSCs in chemically defined culture conditions and use of footprint‐free safer reprogramming strategies have contributed towards the development of clinically relevant cell types. In this review, the role of iPSC‐derived mesenchymal stromal cells (iMSCs) as an alternate source of therapeutically active MSCs has been described. Additionally, we also describe the role of iMSCs in regenerative medical applications, the necessary strategies, and the regulatory policies that have to be enforced to render iMSC's effectiveness in translational medicine.

• MSCs
• hiPSCs
• iMSCs
• induced pluripotent stem cells
• mesenchymal stem cells

• T cell biology
• animal models: murine
• basic (laboratory) research/science
• cellular transplantation (non-islet)
• immunobiology
• immunosuppression/immune modulation
• lymphocyte biology
• molecular biology: mRNA/mRNA expression
• tolerance: mechanisms
• translational research/science

• Bioreactor
• Cardiomyocytes
• Differentiation
• Human pluripotent stem cells
• Process development
• Scale-up

• Animals
• Cell Culture Techniques/instrumentation
• Cell Culture Techniques/methods
• Cell Differentiation
• Humans
• Myocytes, Cardiac/cytology
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/transplantation
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/metabolism
• Pluripotent Stem Cells/transplantation
• Stem Cell Research
• Tissue Engineering/instrumentation
• Tissue Engineering/methods
• Wnt Signaling Pathway

• Cardiac
• Cellular therapy
• Embryonic stem cells
• Pluripotent stem cells
• Progenitor cells
• Tissue regeneration

The prevalence of renal disease continues to increase worldwide. When normal kidney is injured, the damaged renal tissue undergoes pathological and physiological events that lead to acute and chronic kidney diseases, which frequently progress to end stage renal failure. Current treatment of these renal pathologies includes dialysis, which is incapable of restoring full renal function. To address this issue, cell-based therapy has become a potential therapeutic option to treat renal pathologies. Recent development in cell therapy has demonstrated promising therapeutic outcomes, in terms of restoration of renal structure and function impaired by renal disease. This review focuses on the cell therapy approaches for the treatment of kidney diseases, including various cell sources used, as well recent advances made in preclinical and clinical studies.

• Acute kidney injury
• Cell- and tissue-based therapy
• Chronic kidney failure
• Clinical trial
• Evaluation studies

Our previous work reported functional recovery after transplantation of mouse and human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) into rodent models of spinal cord injury (SCI). Although hiPSC-NS/PCs proved useful for the treatment of SCI, the tumorigenicity of the transplanted cells must be resolved before they can be used in clinical applications. The current study sought to determine the feasibility of ablation of the tumors formed after hiPSC-NS/PC transplantation through immunoregulation. Tumorigenic hiPSC-NS/PCs were transplanted into the intact spinal cords of immunocompetent BALB/cA mice with or without immunosuppressant treatment. In vivo bioluminescence imaging was used to evaluate the chronological survival and growth of the transplanted cells. The graft survival rate was 0% in the group without immunosuppressants versus 100% in the group with immunosuppressants. Most of the mice that received immunosuppressants exhibited hind-limb paralysis owing to tumor growth at 3 months after iPSC-NS/PC transplantation. Histological analysis showed that the tumors shared certain characteristics with low-grade gliomas rather than with teratomas. After confirming the progression of the tumors in immunosuppressed mice, the immunosuppressant agents were discontinued, resulting in the complete rejection of iPSC-NS/PC-derived masses within 42 days after drug cessation. In accordance with the tumor rejection, hind-limb motor function was recovered in all of the mice. Moreover, infiltration of microglia and lymphocytes was observed during the course of tumor rejection, along with apoptosis of iPSC-NS/PC-generated cells. Thus, immune rejection can be used as a fail-safe system against potential tumorigenicity after transplantation of iPSC-NS/PCs to treat SCI.

Reprograming somatic cells using exogenetic gene expression represents a groundbreaking step in regenerative medicine. Induced pluripotent stem cells (iPSCs) are expected to yield novel therapies with the potential to solve many issues involving incurable diseases. In particular, applying iPSCs clinically holds the promise of addressing the problems of immune rejection and ethics that have hampered the clinical applications of embryonic stem cells. However, as iPSC research has progressed, new problems have emerged that need to be solved before the routine clinical application of iPSCs can become established. In this review, we discuss the current technologies and future problems of human iPSC generation methods for clinical use.

• Induced pluripotent stem cells
• Cell reprogramming

• Animals
• Diagnostic Imaging
• Humans
• Materials Testing
• Phenotype
• Pluripotent Stem Cells/cytology
• Tissue Engineering/methods
• Tissue Engineering/trends
• Tissue Scaffolds
• Translational Research, Biomedical

• Wellcome Trust

• cell- and tissue-based therapy
• induced pluripotent stem cell
• myocardial infarction
• regenerative medicine
• tissue engineering

• Animals
• Cell Differentiation
• Cells, Cultured
• Coculture Techniques
• Embryo, Mammalian/cytology
• Embryoid Bodies/immunology
• Embryoid Bodies/physiology
• Fibroblasts/cytology
• Induced Pluripotent Stem Cells/immunology
• Induced Pluripotent Stem Cells/transplantation
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred C57BL
• Sertoli Cells/cytology
• Sertoli Cells/immunology
• Spleen/cytology
• T-Lymphocytes/metabolism
• Teratoma/immunology
• Teratoma/pathology

• Induced pluripotent stem cells
• Large animals
• Pluripotent stem cells
• Reprogramming

• allogeneic stem cell therapy
• immunogenicity
• immunomodulatory
• induced pluripotent stem cell
• mesenchymal stromal cell
• transplantation medicine

• Animals
• Cell Culture Techniques
• Cell Differentiation
• Cytokines/metabolism
• Female
• Immunomodulation
• Induced Pluripotent Stem Cells/immunology
• Male
• Mesenchymal Stem Cells/immunology
• Mice
• Mice, Inbred C57BL

• T35 OD010941 NIH HHS
• S10 RR023781 NCRR NIH HHS
• K08 AR060875 NIAMS NIH HHS
• 1K08AR060875-01 NIAMS NIH HHS
• S10RR023781 NCRR NIH HHS

• Human iPS cells; neural progenitor cells
• astrocytes; cell transplantation
• regenerative therapy; ALS

In 2006, we demonstrated that mature somatic cells can be reprogrammed to a pluripotent state by gene transfer, generating induced pluripotent stem (iPS) cells. Since that time, there has been an enormous increase in interest regarding the application of iPS cell technologies to medical science, in particular for regenerative medicine and human disease modeling. In this review article, we outline the current status of applications of iPS technology to cell therapies (particularly for spinal cord injury), as well as neurological disease-specific iPS cell research (particularly for Parkinson’s disease and Alzheimer’s disease). Finally, future directions of iPS cell research are discussed including a) development of an accurate assay system for disease-associated phenotypes, b) demonstration of causative relationships between genotypes and phenotypes by genome editing, c) application to sporadic and common diseases, and d) application to preemptive medicine.

• bioengineered kidney
• endothelial progenitor cell
• kidney regeneration
• renal progenitor cell
• stem cell

• Cell Therapy
• Cellular Immune Response
• Humoral Response
• Induced Pluripotent Stem Cells
• Innate Immunity
• iPSC

• Pluripotent
• Reprogramming
• Retina
• Stem cells
• iPS

• Humans
• Induced Pluripotent Stem Cells/transplantation
• Models, Biological
• Regenerative Medicine/trends
• Retinal Diseases/therapy
• Stem Cell Transplantation/methods
• Stem Cell Transplantation/trends

• MC_PC_U127584475 Medical Research Council
• NIH R01 EY021218 NEI NIH HHS
• MC_U127584475 Medical Research Council
• Wellcome Trust
• R01 EY021218 NEI NIH HHS
• P30 HD003352 NICHD NIH HHS