Molecular Pathway and Cell State Responsible for Dissociation-Induced Apoptosis in Human Pluripotent Stem Cells

作者：Ohgushi Masatoshi; Matsumura Michiru; Eiraku Mototsugu; Murakami Kazuhiro; Aramaki Toshihiro; Nishiyama Ayaka; Muguruma Keiko; Nakano Tokushige; Suga Hidetaka; Ueno Mono; Ishizaki Toshimasa; Suemori Hirofumi; Narumiya Shuh; Niwa Hitoshi; Sasai Yoshiki^*

来源：Cell Stem Cell, 2010, 7(2): 225-239.

DOI：10.1016/j.stem.2010.06.018

Human embryonic stem cells (hESCs), unlike mouse ones (mESCs), are vulnerable to apoptosis upon dissociation. Here, we show that the apoptosis, which is of a nonanoikis type, is caused by ROCK-dependent hyperactivation of actomyosin and efficiently suppressed by the myosin inhibitor Blebbistatin. The actomyosin hyperactivation is triggered by the loss of E-cadherin-dependent intercellular contact and also observed in dissociated mouse epiblast-derived pluripotent cells but not in mESCs. We reveal that Abr, a unique Rho-GEF family factor containing a functional Rac-GAP domain, is an indispensable upstream regulator of the apoptosis and ROCK/myosin hyperactivation. Rho activation coupled with Rac inhibition is induced in hESCs upon dissociation, but not in Abr-depleted hESCs or mESCs. Furthermore, artificial Rho or ROCK activation with Rac inhibition restores the vulnerability of Abr-depleted hESCs to dissociation-induced apoptosis. Thus, the Abr-dependent "Rho-high/Rac-low" state plays a decisive role in initiating the dissociation-induced actomyosin hyperactivation and apoptosis in hESCs.

• 出版日期2010-8-6