Wang Yanglu, Peng Fangqi, Yang Zhihan, Cheng Lin, Cao Jingxiao, Fu Xiaodi, He Huanjing, Cai Ruyi, Zeng Weizhen, Dong Yingshuai, Chen Guanxian, Peng Gongxin, Liuyang Shijia, Wang Guan, Wang Jinlin, Mu Rong, Li Cheng, Guan Jingyang, Deng Hongkui
MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences and MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Nat Chem Biol. 2025 Jan 3. doi: 10.1038/s41589-024-01799-8.
Chemical reprogramming enables the generation of human pluripotent stem (hCiPS) cells from somatic cells using small molecules, providing a promising strategy for regenerative medicine. However, the current method is time consuming, and some cell lines from different donors are resistant to chemical induction, limiting the utility of this approach. Here, we developed a fast reprogramming system capable of generating hCiPS cells in as few as 10 days. This accelerated method enables efficient generation of hCiPS cells with a consistent 100% success rate across 15 different donors, increasing efficiency by over 20-fold within 16 days, especially for previously resistant cells. Mechanistically, we identified KAT3A/KAT3B and KAT6A as key epigenetic obstacles; suppressing these factors facilitated the transition of somatic cells to a poised state by triggering switches in the epigenome. These results highlight the superiority of this system for generating hCiPS cells, which represents a next-generation approach for manufacturing cells for further applications.
化学重编程能够利用小分子从体细胞生成人类多能干细胞（hCiPS细胞），为再生医学提供了一种很有前景的策略。然而，目前的方法耗时较长，并且来自不同供体的一些细胞系对化学诱导有抗性，限制了这种方法的实用性。在此，我们开发了一种快速重编程系统，能够在短短10天内生成hCiPS细胞。这种加速方法能够高效生成hCiPS细胞，在15个不同供体中成功率始终为100%，在16天内效率提高了20多倍，尤其是对于先前有抗性的细胞。从机制上讲，我们确定KAT3A/KAT3B和KAT6A是关键的表观遗传障碍；抑制这些因子通过触发表观基因组中的开关促进了体细胞向就绪状态的转变。这些结果凸显了该系统在生成hCiPS细胞方面的优越性，这代表了一种用于制造细胞以用于进一步应用的下一代方法。
