Authors:
Masatoshi Ohgushi, Michiru Matsumura, Mototsugu Eiraku, Kazuhiro Murakami, Toshihiro Aramaki, Ayaka Nishiyama, Keiko Muguruma, Tokushige Nakano, Hidetaka Suga, Morio Ueno, Toshimasa Ishizaki, Hirofumi Suemori, Shuh Narumiya, Hitoshi Niwa, & Yoshiki Sasai
Summary:
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.
Source:
Cell Stem Cell; Vol. 7, Issue 2, 225-239 (08/06/10)