RRC ID 6135
著者 Ohgushi M, Matsumura M, Eiraku M, Murakami K, Aramaki T, Nishiyama A, Muguruma K, Nakano T, Suga H, Ueno M, Ishizaki T, Suemori H, Narumiya S, Niwa H, Sasai Y.
タイトル Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells.
ジャーナル Cell Stem Cell
Abstract 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.
巻・号 7(2)
ページ 225-39
公開日 2010-8-6
DOI 10.1016/j.stem.2010.06.018
PII S1934-5909(10)00333-4
PMID 20682448
MeSH Animals Apoptosis* / drug effects Cadherins / metabolism Calcium / pharmacology Cell Adhesion / drug effects Embryonic Stem Cells / cytology Embryonic Stem Cells / drug effects Embryonic Stem Cells / enzymology Enzyme Activation / drug effects Extracellular Space / drug effects Extracellular Space / metabolism GTPase-Activating Proteins / metabolism Germ Layers / cytology Germ Layers / drug effects Germ Layers / metabolism Guanine Nucleotide Exchange Factors / metabolism Humans Mice Mitochondria / drug effects Mitochondria / metabolism Myosins / metabolism Pluripotent Stem Cells / cytology* Pluripotent Stem Cells / drug effects Pluripotent Stem Cells / metabolism Signal Transduction* / drug effects rac GTP-Binding Proteins / antagonists & inhibitors rac GTP-Binding Proteins / metabolism rho-Associated Kinases / metabolism
IF 20.86
引用数 252
WOS 分野 CELL BIOLOGY CELL & TISSUE ENGINEERING
リソース情報
ヒトES細胞 KhES-1