Human pluripotent stem cell (hPSC) therapy is a shining star in the field of regenerative medicine. In the 27 years since the first successful acquisition of hPSC, its related technologies have developed rapidly, bringing light to the treatment of many difficult diseases. hPSC includes human embryonic stem cells (hESC), which can produce non-cancerous human cells in large quantities to provide sufficient resources for cell therapy, and human induced pluripotent stem cells (hiPSC), which break the shackles of traditional cell sources, both of which theoretically offer unlimited possibilities for regenerative medicine.

Pluripotent stem - cell-derived therapies in clinical trial:  Published in the journal Cell Stem Cell, the 2025 update comprehensively reviews and analyzes the progress of clinical trials of hPSC therapy worldwide as of December 2024, providing an important reference for understanding the current research status, challenges and future development direction in this field.

Early test

The year 1998

The successful extraction of hESC allows humans to produce non-cancerous human cells and obtain therapeutic human cell types, laying the foundation for regenerative cell therapy.

2007

In 2007, Shinya Yamanaka and Junying Yu published important results in the journals Cell and Science, respectively, reporting major studies that successfully transformed human skin cells into hiPSC under in vitro culture conditions. The emergence of hiPSC makes it possible to reprogram somatic cells to create autologous cell lines and HLA homozygous donor cell lines to meet the need of reducing immunosuppression.

From 2007 to 2012

With the improvement of the training system, hESC libraries under GMP conditions have been established in Israel, Singapore and the United Kingdom.

The year 2008

Geron Corporation has successfully obtained a New Drug Clinical Trial Application (IND) approval from the U.S. Food and Drug Administration (FDA) to initiate a Phase I clinical trial of an hPSC derived product using a HESC-derived oligodendrocyte progentory product (GRN-OPC1) for the treatment of thoracic spinal cord injuries.

From 2011 to 2015

The hPSC products entering clinical trials at this stage are all based on retinal pigment epithelial cells (RPE) for the treatment of eye diseases. Advanced Cell Technology's MA09-hRPE product was tested in five trials during this period.

The year 2013

Masayo Takahashi's team at the RIKEN Research Institute in Japan developed the first autogenous hiPSC product and conducted clinical trials for the treatment of age-related macular degeneration (AMD) in Japan, but did not proceed due to manufacturing complexity and high cost.

Clinical Trial Panorama

As of December 2024, 115 interventional clinical trials have been approved worldwide, testing 83 hPSC products for 34 indications, and more than 1,200 patients have been treated with hPSC products, with a cumulative use of more than 10¹¹  cells.

The trials were distributed across the globe, with the United States, Japan, and China being the main centers of research, with 52, 17, and 21 hPSC clinical trials, respectively.

Most of these trials are in Phase I and I/II, focusing on safety and feasibility, with only a few trials beginning to explore the effectiveness of the product.

Different cell sources

hESC, Human embryonic stem cells; hiPSC-Allo, allogeneic human induced pluripotent stem cells; hiPSC-HLA: induced pluripotent stem cells matched with human leukocyte antigen; hiPSC-Auto: autologous human induced pluripotent stem cells; hpESC, human parthenogenetic embryonic stem cells; SCNT: Somatic cell nuclear transfer

From 2010 to 2014, the trial mainly used hESC. From 2013 to 2019, other cell sources such as hiPSC-Auto and hiPSC-HLA gradually emerged and increased, especially hiPSC-Auto increased significantly in some years. Between 2020 and 2024, the number of product trials based on hiPSC will increase significantly, and hiPSC will become the main direction of research in pluripotent stem cell therapy.

In all the cell sources tested, hiPSC accounted for the largest proportion, reaching 56%, and was the most important cell source. Among them, hiPSC-Allo accounted for 35%, hiPSC-Auto accounted for 13% and hiPSC-HLA accounted for 3%. hESC (42%), hpESC (1%) and SCNT (1%) followed. In general, it shows that hiPSC has broad application prospects.

Products in different fields

The main types of hPSC products are: Ocular (21), central nervous system (CNS, 20), heart /Muscle (Cardio/Muscle, 8), Immune/Blood (16), Endocrine (8), and Stromal (10).

Early hPSC trials focused on the ocular and central nervous system areas and were limited in number. Since 2015, the number of trials has increased significantly and the product types have become more diverse, covering multiple areas such as immunology/blood and endocrinology. The cumulative number of trials for all kinds of products increased, especially for eye and central nervous system products, which developed rapidly in the early stage. While the heart/muscle, immune/blood, endocrine and other types of products, although the initial test is less, but the later growth is obvious; Although the cumulative test number of matrix products is relatively small, it also shows a certain growth trend.

Eye disease

AMD: Age-related macular degeneration; SMD: Stargart macular degeneration; RP: retinitis pigmentosa; RID: retinal pigment epithelial lesion; LSCD: limbal stem cell deficiency; BK: bullous keratopathy; PPD: Primary photoreceptor disease; The Cornea; Photoreceptors: photoreceptor cells; RPE: retinal pigment epithelial cells

Ocular diseases are one of the first areas to conduct clinical trials of HPSC-derived therapies, focusing on RPE dysfunction and degenerative diseases such as AMD and SMD. AMD has been the most extensively studied in ocular hPSC trials. Other indications such as SMD, RP, etc., also have a certain number of trials, but the proportion is relatively small.

Dry AMD and SMD

In 2011, Advanced Cell Technology (later acquired by Astellas) initiated the first clinical trial of a HESC-derived RPE cell suspension (MA09-hRPE) for the treatment of SMD and dry AMD. The results showed that some patients had improved vision, but the overall effect was limited. Since then, multiple teams have continued to explore different forms of RPE cell tablets and suspensions, such as the Regenerative Patch Technologies' Cynata iPSC-MSC for graft-versa-host disease and osteoarthritis, And autologous hiPSC-RPE cell tablets from the RIKEN Institute.

Wet AMD

In 2013, Masayo Takahashi's team at the RIKEN Research Institute in Japan first used autologous HiPSC-derived RPE cell tablets to treat wet AMD, showing good transplant survival and visual stability. Since then, similar studies have been carried out by various teams, such as the hESC-RPE cell tablets at Moorfields Eye Hospital and the hiPSC-RPE cell suspension at Kobe City Eye Hospital.

Other eye indications

From 2019 to 2023, iSTEM in France, Kobe City Hospital in Japan, and Osaka University in Japan respectively carried out clinical trials for RP, LSCD, BK and other diseases, with no serious adverse events and improved disease symptoms. BlueRock Therapeutics receives IND approval for clinical trial using HIPSC-derived photoreceptor cells to treat primary photoreceptor diseases.

Central nervous system indications

PD: Parkinson's disease; SCI: Spinal cord injury; Stroke: a stroke; Epilepsy: Epilepsy.

ALS: ALS; DA cells: Dopamine cells; NSCs, neural stem cells; Neurons: Interneurons; OPCs: oligodendrocyte progenitor cells;

Astrocytes: astrocytes

Central nervous system diseases are another important application area of HPSC-derived therapies, mainly including PD, SCI and epilepsy. In the central nervous system hPSC test, there are more studies on Parkinson's disease. Other diseases, such as SCI, have also been tested, but the proportion is relatively low.

PD

In 2015, China launched the first clinical trial of HESC-derived dopaminergic progenitor cells to treat PD. Since then, Australia has carried out trials using parthenogenetic stem cells in 2016, and Japan, the United States, Sweden, and South Korea have also carried out clinical trials of different products, and some trials have shown good safety and symptoms improvement in some patients. At present, there are also more domestic enterprises in the field of PD treatment layout of the relevant research and development pipeline, such as Zhongsheng Traceability, Ruijian Medicine, Yuesai biology and Shize biology. BlueRock Therapeutics initiated a trial of HESC-derived midbrain dopamine neuron products for administration in 2021 and demonstrated good tolerance in the Phase I trial with no drug-related serious adverse events over 24 months. The company plans to initiate a Phase III registered clinical trial called Expdianite-2 in the first half of 2025 to become the fastest advancing company in the field of hPSC treatment of PD.

SCI

GRN-OPC1, a HESC-derived oligodendrocyte progentory product developed by Geron in 2010 for the treatment of thoracic segment SCI, was the first hPSC product to enter clinical trials. Preliminary trials showed that its safety was good, but it did not significantly improve patients due to low cell dose. The technique was subsequently acquired by Asterias Biotherapeutics and started in 2015 as AST-OPC1 in another Phase I/II dose-escalation trial in patients with cervical spine SCI, which demonstrated recovery of neurological function in some patients. In addition, clinical trials have also been conducted at Keio University in Japan and S.Biomedics in South Korea.

epilepsy

In 2022, Neurona Therapeutics initiated the first clinical trial of a HESC-derived inhibitory GABAergic interneuron product, NRTX-1001, for the treatment of drug-resistant focal epilepsy with positive results and has expanded the trial.

Other central nervous system indications

In 2018, KadimaStem in Israel conducted a trial of HESC-derived astrocytes for the treatment of amyotrophic lateral sclerosis. 2021 Stanford University trial to treat ischemic subcortical stroke; In 2024, UC Irvine developed a neural stem cell product for the treatment of Huntington's disease, which has been approved by the FDA but has not yet begun clinical trials.

Heart disease

Cell replacement therapy using a variety of cell types is currently being tested on patients with myocardial infarction and chronic heart failure. After a myocardial infarction, up to 1 billion heart muscle cells are lost and replaced by non-contractile scar tissue, a process that can secondary progress to chronic heart failure. To this end, several laboratories are developing HPSC-derived cardiomyocytes to improve cardiac systolic function.

In 2013, Philippe Menasche's team transplanted HESC-derived cardiomyocyte progenitor cells into the heart surface of patients with myocardial infarction for the first time, showing good tolerance and improved cardiac function in some patients. Since then, several teams have developed different forms of cardiomyocyte tablets, spheres and suspensions, such as hiPSC cardiomyocyte tablets from Osaka University and HS-001 from Heartseed, with some trials showing signs of improved heart function.

diabetes

Type 1 diabetes is caused by the autoimmune mediated destruction of insulin-producing beta cells in the endocrine islets of the pancreas. Given its early onset and serious health consequences, the use of cadaver source islets for transplantation has been explored as a treatment option since the 1970s.

In 2014, Viacyte initiated the first clinical trial of HESC-derived pancreatic endoderm cells (PEC-01) for the treatment of type 1 diabetes. Early trials resulted in low survival of transplanted cells due to equipment design problems, and the results of subsequent improved design trials have not yet been published. In 2021, Fortei Pharmaceuticals initiated a trial of unencapsulated HESC-derived cell VX-880 for the treatment of PD, and its phase I/II clinical trial showed signs of islet cell implantation, with some patients achieving insulin independence. In November 2024, Fortey announced that it was moving from the initial Phase I/II trial to the pivotal Phase I/II/III trial, bringing the VX-880 product one step closer to a possible market launch.

In 2023, Deng Hongkui's team at Tianjin First Central Hospital in China used a clinical trial using autologous islet-like cells to avoid graft rejection, reporting that the first patient achieved insulin independence.

Liver disease

Psc-derived hepatocytes for the treatment of acute liver failure are one of the most difficult products to develop. For patients with acute liver failure, giving PSC-derived liver cells as a bridging therapy before the liver regenerates or becomes available for transplant could be a life-saving intervention.

Research into the treatment of liver disease based on pluripotent stem cells (hPSC) is currently in the exploratory stage, with two clinical trials underway.

Xiangya Hospital of Central South University in China is testing HESC-derived liver cells on patients with liver failure and plans to enroll 10 patients; The National Center for Child Health and Development in Japan tested HESC-liver cells in 2 newborn patients with urea cycle disorders. However, specific product information, such as dosage and immunosuppressive requirements, was not disclosed in the two trials, and safety or efficacy data have not been reported.

Immunization and blood products

blood cancer: leukemia; solid tumor; solid tumor; ovarian cancer: Ovarian cancer; COVID-19: COVID-19; SLE: Systemic lupus erythematosus; NSCLC: non-small cell lung cancer; NK cells: natural killer cells; T cell; DC: Dendritic cell; NKT: Natural killer T cells

Immune and blood disorders are another important application area for HPSC-derived therapies, mainly for ovarian cancer, leukemia, solid tumors, etc. CAR T therapy has a significant effect on patients with refractory hematological malignancies, but there are some problems such as high cost, unstable cell quality and difficult manufacturing. Therefore, the development of allogeneic readily available HPSC-derived NK and T cell products has become a research direction.

NK cell products

Fate Therapeutics' FT500 is the first hiPSC-NK cell product for patients with advanced solid tumors. Subsequent products, such as FT516 and FT538, have been genetically edited to enhance cytotoxicity and persistence, and introduce chimeric antigen receptors for specific diseases. Preliminary data show safety and tolerability, and some leukemia patients have good efficacy. Century Therapeutics' HPSC-derived CAR19-iNK cell product has demonstrated a favorable safety profile and moderate efficacy in trials in patients with relapsed or refractory CD19-positive B-cell malignancies. In addition, the anti-GPC3 NK cell products developed in Japan are undergoing relevant clinical trials, but there are few data at present. Two IPSC-NK-based therapeutic pipelines traced by Zhongsheng, a domestic biotechnology company, have entered phase I/II clinical trials for myelodysplastic syndrome and prevention of recurrence of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), respectively. The former is the first approved clinical IPSC-derived NK cell therapy in China. The clinical trial application of QN-019a cell injection based on iPSC-NK for relapsed/refractory B acute lymphoblastic leukemia was accepted on May 6, 2023.

T cell products

While HIPSC-derived T cell product development is more challenging, Fate Therapeutics' FT819 eliminates endogenous T cell receptors through gene editing, reduces graft-versus-host disease (GvHD) risk, and has shown a favorable safety profile in patients with relapsed/refractory B-cell lymphoma. At the same time, FT819 has achieved drug-free clinical remission in the first patient in the trial for the treatment of SLE, which brings hope for future B-cell targeted therapy for autoimmune diseases.

Dendritic cell products

The HESC-derived dendritic cell product GRN-VAC02 (now renamed AST-VAC2) developed by Geron for the treatment of non-small cell lung cancer has been shown in trials to be well tolerated and to induce an immune response.

Platelet products

Ipsc-derived platelet products show potential in the treatment of thrombocytopenia, and Japanese companies CiRA and Megakaryon successfully tested their IPSC-derived platelet products iPLAT1 and MEG-002 in patients, respectively, with no safety concerns observed.

Matrix products

Mesenchymal stromal cells (MSCs), which can be derived from bone marrow, adipose tissue, and cord blood, have been used in clinical trials since the mid-1990s. Despite more than 1,000 clinical studies, only OSSM-001 for the treatment of perianal fistula Crohn's disease is currently approved by the FDA.

In view of the challenges in the manufacture of autologous MSCs, HPSC-derived MSCs have become a research hotspot. Cynata Therapeutics Australia has been testing hPSC-MSC products since 2017 for the treatment of GvHD, diabetic foot ulcers, osteoarthritis and other conditions. In a Phase I trial for the treatment of GvHD, the CYP-001 product showed good tolerance and partial remission in 15 patients with acute steroid-resistant GvHD. In addition, the Korean team used hESC-MSC to treat interstitial cystitis, and some patients showed improvement in symptoms. The hESC-MSC product developed by ImStem is undergoing clinical trials in multiple sclerosis. Clinical trials initiated by multiple teams for PSC-MSC in COVID-19 patients and Cynata Therapeutics' Phase III trial for osteoarthritis with CYP-004 have not reported clinical results. In China, the pipeline of IPSC-MSC-based NCR100 injection for the treatment of knee osteoarthritis has entered the phase II clinical trial stage, and is the first approved clinical IPSC-derived MSC cell therapy in China. The IPSC-MSC-based NCR101 injection was IND approved in February 2025 for the treatment of interstitial lung disease, becoming the world's first genetically modified IPSC-derived MSC therapeutic product.

With the continuous advancement of clinical trials of hPSC, its application fields have gradually expanded from the initial focus on central nervous system and eye diseases to multiple fields, showing a diversified development trend. The immunology and blood cell product category now accounts for 31% of all patients treated, and reliable efficacy data is emerging for the treatment of diseases such as diabetes, epilepsy, PD, and AMD. However, the development of this field still faces challenges such as Phase II/III trial design and Phase III trial design, production and technology, pricing and marketing. In order for this innovative therapy to move from the laboratory to clinical application and truly benefit patients, these challenges must be effectively addressed. Only by overcoming these obstacles can we ensure that hPSC therapy can successfully enter the clinical stage and bring real therapeutic effects to patients. Therefore, all parties need to work together to promote technological advances, optimize production processes, and develop reasonable pricing strategies to promote the successful conversion and widespread use of hPSC therapies.