title: Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells.
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.
authors.affiliation: Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ohgushi
authors.forename: Michiru
authors.initials: M
authors.lastname: Matsumura
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Eiraku
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Murakami
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aramaki
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Muguruma
authors.forename: Tokushige
authors.initials: T
authors.lastname: Nakano
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Suga
authors.forename: Morio
authors.initials: M
authors.lastname: Ueno
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Ishizaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Suemori
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Niwa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sasai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005855:Germ Layers / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C082659:ABR protein, human; D015820:Cadherins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D054460:rho-Associated Kinases; D009218:Myosins; D020744:rac GTP-Binding Proteins; D002118:Calcium