Published online before print May 31, 2007, doi: 10.1161/CIRCRESAHA.106.147264
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Submitted on December 21, 2006
Revised on May 16, 2007
Accepted on May 18, 2007
Stage-Specific Role of Endogenous Smad2 Activation in Cardiomyogenesis of Embryonic Stem Cells
Ryoji Kitamura ;
From the Department of Cardiovascular Medicine (R.K., T.T., N.N, K.I., S.A., H.M.) and Department of Inflammation and Immunology (T.Y.), Kyoto Prefectural University of Medicine; Department of Experimental Therapeutics (R.K., T.T., N.N, K.I., S.A., T.U., H.M., H.O.), Translational Research Center, Kyoto University Hospital; and Department of Biochemistry and Molecular Pathophysiology (H.U.), University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan.
* To whom correspondence should be addressed. E-mail: ttaka{at}koto.kpu-m.ac.jp.
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-
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-, and inhibition of transforming growth factor--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- negatively regulates cardiomyogenesis through Smad2 activation by modulating proliferation and differentiation of cardiac myocytes.
Key words: embryonic stem cells • cardiomyogenesis • Smad2 • TGF-
•
differentiation
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