Kitamura Ryoji, Takahashi Tomosaburo, Nakajima Norio, Isodono Koji, Asada Satoshi, Ueno Hikaru, Ueyama Tomomi, Yoshikawa Toshikazu, Matsubara Hiroaki, Oh Hidemasa
Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
Circ Res. 2007 Jul 6;101(1):78-87. doi: 10.1161/CIRCRESAHA.106.147264. Epub 2007 May 31.
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.
研究了Smads及其特定配体在胚胎干细胞心肌生成过程中的作用。Smad2在心脏分化的早期和晚期呈双峰激活，而Smad1在中期之后被激活。Nodal和Cripto在早期表达，随后下调，而转化生长因子-β和激活素仅在晚期表达。SB-431542对早期Smad2激活的抑制导致内胚层和中胚层诱导的完全抑制，但增强了神经外胚层分化，随后心肌生成不良，而仅在晚期进行抑制则促进心肌生成。Smad2在晚期对心肌生成的抑制作用主要由转化生长因子-β介导，抑制转化生长因子-β介导的Smad2激活导致分化的心肌细胞具有更大的复制潜能，并增强非心肌细胞向心肌细胞的分化。因此，内源性Smad2激活在早期内胚层和中胚层诱导中是不可或缺的。在晚期，内源性转化生长因子-β通过调节心肌细胞的增殖和分化，通过Smad2激活对心肌生成产生负调控作用。
