Frontiers in Cell and Developmental Biology · Oct 30, 2026
The Translational Journey of Human Pluripotent Stem Cells
By Vasanth Thamodaran, Roja Nayak K, Nimisha Goswami et al.
Human pluripotent stem cells (hPSCs), comprising embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have emerged as a versatile platform connecting developmental biology with disease modelling, drug discovery, and regenerative medicine. Their capacity for indefinite self-renewal and differentiation into derivatives of all three germ layers provides an essentially renewable source of human cells that are otherwise inaccessible from patients. In this review, we discuss the biological principles governing hPSC identity, with emphasis on the transcriptional, epigenetic, metabolic, and extracellular signalling networks that regulate pluripotency and the distinct features of naive and primed states. We further examine culture systems for maintaining pluripotency and directed differentiation strategies for generating lineage-specific cell types. The application of hPSCs to disease modelling and therapeutic discovery is considered through two-dimensional cellular models and increasingly sophisticated three-dimensional organoids and organoid-on-chip systems, which provide progressively greater tissue complexity and physiological relevance. We also highlight the integration of CRISPR-based genome editing with hPSC platforms to generate isogenic disease models, establish genotype–phenotype relationships, identify therapeutic targets, and enable precise correction of disease-associated variants. Finally, we review the emerging clinical applications of hPSC-derived cell therapies and clinical translation, which remains constrained by challenges related to genomic stability, cellular heterogeneity and maturation, immune compatibility, tumorigenicity, manufacturing, and scalability. Addressing these challenges through improved differentiation, quality control, genome engineering, and scalable manufacturing will be essential for translating the broad potential of hPSCs into safe, reproducible, and accessible clinical therapies.