title: Stage-specific role of endogenous Smad2 activation in cardiomyogenesis of embryonic stem cells.
abstract: The role of Smads and their specific ligands during cardiomyogenesis in ES cells was examined. Smad2 was activated bimodally in the early and late phases of cardiac differentiation, whereas Smad1 was activated after the middle phase. Nodal and Cripto were expressed in the early stage and then downregulated, whereas transforming growth factor-beta and activin were expressed only in the late phase. Suppression of early Smad2 activation by SB-431542 produced complete inhibition of endodermal and mesodermal induction but augmented neuroectodermal differentiation, followed by poor cardiomyogenesis, whereas inhibition during the late phase alone promoted cardiomyogenesis. Inhibitory effect of Smad2 on cardiomyogenesis in the late phase was mainly mediated by transforming growth factor-beta, and inhibition of transforming growth factor-beta-mediated Smad2 activation resulted in a greater replicative potential in differentiated cardiac myocytes and enhanced differentiation of nonmyocytes into cardiac myocytes. Thus, endogenous Smad2 activation is indispensable for endodermal and mesodermal induction in the early phase. In the late phase, endogenous transforming growth factor-beta negatively regulates cardiomyogenesis through Smad2 activation by modulating proliferation and differentiation of cardiac myocytes.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kitamura
authors.forename: Tomosaburo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Norio
authors.initials: N
authors.lastname: Nakajima
authors.forename: Koji
authors.initials: K
authors.lastname: Isodono
authors.forename: Satoshi
authors.initials: S
authors.lastname: Asada
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ueno
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Oh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology / Q000502:physiology; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism* / Q000502:physiology
chemical_list: D051899:Smad2 Protein; C497783:Smad2 protein, mouse