A Fast Chemical Reprogramming System to Generate Human Pluripotent Stem Cells [RNA-seq]

Chemical reprogramming enables the generation of human pluripotent stem cells (hCiPSCs) from somatic cells using small molecules, providing a novel and promising strategy for regenerative medicine. However, the current method for generating hCiPSCs is time consuming, and some cell lines from different donors are resistant to chemical induction, significantly limiting the utility of these cells for personalized medicine. Here, we developed a fast-reprogramming system capable of generating hCiPSCs in as few as 10 days. This accelerated method enables efficient generation of hCiPSCs with a consistent 100% success rate across 15 different donors. In particular, the efficiency of reprogramming within 16 days for cells refractory to previously reported protocols increased more than 30-fold. Mechanistically, we identified KAT3A/B and KAT6A as key epigenetic obstacles, as suppression of these factors facilitated the transition of somatic cells to a poised state by triggering switches in the epigenome, a process essential for this fast-reprogramming system. These results highlight the superiority of this novel system for generating hCiPSCs, which represents a next-generation approach for manufacturing cells for clinical applications. This work also advances our understanding of human cell reprogramming and paves the way for broader applications of chemical reprogramming in regenerative medicine.