Tzu-Yu Chen, Yu-Xiu Lin, & Thai-Yen Ling, Ph.D.
Graduate Institute of Pharmacology, College of Medicine
National Taiwan University, Taipei, Taiwan

Human induced pluripotent stem cells (iPSCs) are pluripotent stem cells generated through the reprogramming of differentiated somatic cells into an embryonic stem cell-like state via the ectopic expression of defined transcription factors. Due to their unlimited self-renewal capability and multilineage differentiation potential, iPSCs have emerged as one of the most important advances in regenerative medicine and stem cell biology over the past two decades [1]. In 2006, Kazutoshi Takahashi and Shinya Yamanaka first demonstrated that differentiated somatic cells could be reprogrammed into a pluripotent state through the ectopic expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC.

This pioneering discovery fundamentally transformed stem cell research by providing a novel strategy for generating pluripotent stem cells from adult somatic cells. Following this milestone, human iPSCs were independently established by Yamanaka’s group and James Thomson’s group in 2007, further accelerating the development of regenerative medicine and personalized therapeutics [2]. Compared with embryonic stem cells (ESCs), iPSCs provide an alternative source of pluripotent stem cells while largely avoiding the ethical concerns associated with embryo destruction. Similar to ESCs, iPSCs possess the ability to differentiate into cell types derived from all three germ layers, including ectoderm, mesoderm, and endoderm.

Due to these unique biological characteristics, iPSCs have become highly promising platforms for disease modeling, drug discovery, toxicological studies, regenerative medicine, and personalized therapy.

Unlike conventional immortalized cell lines, patient-derived iPSCs retain the donor’s genetic background, allowing researchers to better investigate disease pathogenesis, genetic heterogeneity, and patient-specific therapeutic responses. Consequently, iPSC-based disease models have been widely applied in studies of neurodegenerative diseases, cardiovascular disorders, metabolic diseases, liver diseases, and inherited genetic disorders [3].

Furthermore, advances in directed differentiation technologies have enabled the efficient generation of various functional cell types from iPSCs, including cardiomyocytes, hepatocytes, neurons, pancreatic β cells, retinal cells, and mesenchymal stromal cells [4]. These developments have substantially expanded the translational potential of iPSC-derived products in tissue engineering, organ regeneration, and cell replacement therapies.

In parallel with advances in differentiation technologies, considerable efforts have also been devoted to improving the safety and clinical applicability of iPSC-based platforms. Early reprogramming strategies primarily relied on integrating viral vectors, which raised concerns regarding insertional mutagenesis and genomic instability. To overcome these limitations, several non-integrating approaches, including episomal plasmids, Sendai virus, synthetic mRNA, microRNAs, and small molecules, have subsequently been developed to enhance reprogramming efficiency and biosafety [5].

Moreover, continuous improvements in large-scale cell manufacturing, quality control systems, and standardized differentiation protocols have further facilitated the clinical translation of iPSC-derived therapeutics.

Importantly, the clinical development of iPSC-based therapies has recently achieved a major milestone. In 2026, Japan granted conditional approval for the world’s first iPSC-derived therapeutic products, including iPSC-derived dopaminergic progenitor cells for Parkinson’s disease and iPSC-derived cardiomyocyte patches for ischemic heart failure treatment [6].

These landmark approvals highlight the growing feasibility and translational potential of iPSC-based regenerative medicine in clinical settings. Nevertheless, several challenges still remain before the widespread clinical implementation of iPSC-derived therapies can be fully realized, including tumorigenicity, immune rejection, incomplete differentiation, genomic instability, batch-to-batch variability, and large-scale manufacturing limitations. Therefore, further studies are still required to improve the safety, stability, reproducibility, and standardization of iPSC-derived products for future biomedical and clinical applications.

References

• Qu, X., Liu, T., Song, K., Li, X., & Ge, D. (2012). Induced pluripotent stem cells generated from human adipose-derived stem cells using a non-viral polycistronic plasmid in feeder-free conditions. PloS one, 7(10), e48161. https://doi.org/10.1371/journal.pone.0048161
• Cerneckis, J., Cai, H., & Shi, Y. (2024). Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Signal Transduction and Targeted Therapy, 9(1), 112. https://doi.org/10.1038/s41392-024-01809-0
• Liu, C., Oikonomopoulos, A., Sayed, N., & Wu, J. C. (2018). Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development, 145(5), dev156166. https://doi.org/10.1242/dev.156166
• Ye, Z., Zhao, H., & Ye, X. (2025). Application potential of induced pluripotent stem cells in the research and treatment of autoimmune diseases. Molecular Medicine Reports, 32(6), 333. https://doi.org/10.3892/mmr.2025.13698
• Cieślar-Pobuda, A., Knoflach, V., Ringh, M. V., Stark, J., Likus, W., Siemianowicz, K., … & Łos, M. J. (2017). Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1864(7), 1359-1369. https://doi.org/10.1016/j.bbamcr.2017.04.017
• Marshall, A. (2026). World’s first two iPSC therapies in Japan. nature biotechnology, 44, 495-502. https://doi.org/10.1038/s41587-026-03105-4