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.

我们最近展示了将人类体细胞化学重编程为多能干细胞 (hCiPSC)，这为细胞命运操纵提供了一种可靠的方法。然而，这种化学方法的实用性目前受到缓慢动力学的阻碍。在这里，通过筛选小分子助推器并系统地优化原始条件，我们建立了一个稳健的、化学定义的重编程方案，大大缩短了诱导时间，从大约 50 天缩短到最少 16 天，并实现高度可重复和高效的生成来自所有 17 位测试供体的 hCiPSC。我们发现，这种优化的方案通过在早期促进细胞增殖和氧化磷酸化代谢活动，实现了更直接的重编程过程。