Reference - Detail
RRC ID | 6135 |
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Author | 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. |
Title | Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells. |
Journal | 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. |
Volume | 7(2) |
Pages | 225-39 |
Published | 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 |
Times Cited | 252 |
WOS Category | CELL BIOLOGY CELL & TISSUE ENGINEERING |
Resource | |
Human embryonic stem cells | KhES-1 |