Highly efficient and rapid generation of human pluripotent stem cells by chemical reprogramming

We recently demonstrated the chemical reprogramming of human somatic cells to pluripotent stem cells (hCiPSCs), which provides a robust approach for cell fate manipulation. However, the utility of this chemical approach is currently hampered by slow kinetics. Here, by screening for small molecule boosters and systematically optimizing the original condition, we have established a robust, chemically defined reprogramming protocol, which greatly shortens the induction time from ∼50 days to a minimum of 16 days and enables highly reproducible and efficient generation of hCiPSCs from all 17 tested donors. We found that this optimized protocol enabled a more direct reprogramming process by promoting cell proliferation and oxidative phosphorylation metabolic activities at the early stage. Our results highlight a distinct chemical reprogramming pathway that leads to a shortcut for the generation of human pluripotent stem cells, which represents a powerful strategy for human cell fate manipulation. [Display omitted] •A robust three-stage chemically defined reprogramming protocol•Highly reproducible and efficient generation of hCiPS cells•Cells undergo a more direct and rapid molecular trajectory toward pluripotency•A unique metabolic reprogramming fuel cell proliferation and cell fate transition Chemical reprogramming provides a robust approach for cell fate manipulation. Here, Deng and colleagues developed a highly reproducible and efficient chemical reprogramming method for the induction of human pluripotent stem cells and revealed increased cell proliferation and OXPHOS activity early in this reprogramming process.