Wang Wenqian, Zhu Yanling, Huang Ke, Shan Yongli, Du Juan, Dong Xiaoya, Ma Ping, Wu Penafei, Zhang Jian, Huang Wenhao, Zhang Tian, Liao Baojian, Yao Deyang, Pan Guangjin, Liu Jiajun
Department of Hematology, Sun Yat-Sen University, Guangzhou, China.
Chinese Academy of Sciences Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; and.
FASEB J. 2017 Mar;31(3):1130-1140. doi: 10.1096/fj.201600782R. Epub 2016 Dec 13.
Dissociation-induced apoptosis is a striking phenomenon in human embryonic stem cells (hESCs), but not in naive mouse ESCs. Rho-associated kinase-dependent actin-myosin hyperactivation is an underlying mechanism that triggers apoptosis in dissociated hESCs; however, in this study, we show that the -mediated senescence pathway is another mechanism to cause apoptosis in individualized hESCs. We show that P16 and P14 are immediately induced in hESCs upon dissociation, but not in mouse ESCs. Overexpression of BMI1, a suppressor for , greatly promotes survival and cloning efficiency of individualized hESCs mechanistically direct binding the H3K27me3-marked locus. Forced expression of BMI1 in hESCs does not reduce the actin-myosin activation that is triggered by dissociation, which indicates it is an independent pathway for hESC survival. Furthermore, dual inhibition of both and actin-myosin hyperactivation enables successful passaging of hESCs gelatin, a nonbioactive matrix. In sum, we provide an additional mechanism that underlies cell death in individualized hESCs that might help to fully understand the differential cell characteristics between naive and primed ESCs.-Wang, W., Zhu, Y., Huang, K., Shan, Y., Du, J., Dong, X., Ma, P., Wu, P., Zhang, J., Huang, W., Zhang, T., Liao, B., Yao, D., Pan, G., Liu, J. Suppressing P16 and P14 pathways overcomes apoptosis in individualized human embryonic stem cells.
解离诱导的细胞凋亡是人类胚胎干细胞（hESCs）中一种显著的现象，但在未分化的小鼠胚胎干细胞中则不然。Rho相关激酶依赖性肌动蛋白-肌球蛋白过度激活是触发解离的hESCs凋亡的潜在机制；然而，在本研究中，我们表明p16和p14介导的衰老途径是导致单个hESCs凋亡的另一种机制。我们发现hESCs在解离后立即诱导p16和p14表达，但在小鼠胚胎干细胞中则不会。BMI1是p16和p14的抑制因子，其过表达通过直接结合H3K27me3标记的p16和p14基因座，极大地提高了单个hESCs的存活率和克隆效率。在hESCs中强制表达BMI1不会降低由解离触发的肌动蛋白-肌球蛋白激活，这表明它是hESCs存活的独立途径。此外，对p16和p14以及肌动蛋白-肌球蛋白过度激活的双重抑制能够使hESCs在明胶（一种无生物活性的基质）上成功传代。总之，我们提供了一种导致单个hESCs细胞死亡的额外机制，这可能有助于充分理解未分化和已分化胚胎干细胞之间不同的细胞特征。-王，W.，朱，Y.，黄，K.，单，Y.，杜，J.，董，X.，马，P.，吴，P.，张，J.，黄，W.，张，T.，廖，B.，姚，D.，潘，G.，刘，J.抑制p16和p14途径可克服单个化人类胚胎干细胞的凋亡 。
