Li Jiayu, Lin Xiwen, Xie Liangfu, Zhao Jingru, Han Chunsheng, Deng Hongkui, Xu Jun
Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University Health Science Center, Peking University, Beijing 100191, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Life Med. 2023 Oct 20;2(4):lnad037. doi: 10.1093/lifemedi/lnad037. eCollection 2023 Aug.
Regulation of totipotency and naïve pluripotency is crucial for early human embryo development. However, the mechanisms of naïve pluripotency and totipotency regulation in humans, especially the signaling pathways involved in these processes, remain largely unknown. Here, using the conversion of human extended pluripotent stem cells (hEPSCs) to naïve pluripotent stem cells as a model, we performed a CRISPR/Cas9-based kinome knockout screen to analyze the effect of disrupting 763 kinases in regulating human naïve pluripotency. Further validation using small molecules revealed that the inhibition of ErbB family kinases promoted the transition of hEPSCs to human naïve pluripotent stem cells. More importantly, chemical inhibition of the ErbB family also promoted induction of totipotent signatures in human pluripotent cells under different culture conditions. Our findings provide new mechanistic insights into the regulation of naïve pluripotency and totipotency in humans.
全能性和原始多能性的调控对人类早期胚胎发育至关重要。然而，人类中原始多能性和全能性调控的机制，尤其是这些过程中涉及的信号通路，仍 largely 未知。在此，我们以人类扩展多能干细胞（hEPSCs）向原始多能干细胞的转化为模型，进行了基于CRISPR/Cas9的激酶组敲除筛选，以分析破坏763种激酶对调控人类原始多能性的影响。使用小分子的进一步验证表明，抑制ErbB家族激酶可促进hEPSCs向人类原始多能干细胞的转变。更重要的是化学抑制ErbB家族也促进了在不同培养条件下人类多能细胞中全能性特征的诱导。我们的研究结果为人类原始多能性和全能性的调控提供了新的机制见解。
