Stage-specific role of endogenous Smad2 activation in cardiomyogenesis of embryonic stem cells
Stage-specific role of endogenous Smad2 activation in cardiomyogenesis of embryonic stem cells
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DOI：
10.1161/circresaha.106.147264
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发表时间：
2007-07-06
影响因子：
20.1
通讯作者：
Oh, Hidemasa
中科院分区：
文献类型：
--
作者：
Kitamura, Ryoji;Takahashi, Tomosaburo;Oh, Hidemasa
研究了Smads及其特异性配体在ES细胞心肌发生过程中的作用。Smad 2在心脏分化的早期和晚期被双峰激活，而Smad 1在中期后被激活。Nodal和Cripto在早期表达，然后下调，而转化生长因子-β和激活素仅在晚期表达。SB- 431542对早期Smad 2激活的抑制产生了对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，随后是较差的心肌形成，而在晚期阶段单独抑制促进了心肌形成。Smad 2对晚期心肌形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Smad 2活化导致分化的心肌细胞具有更大的复制潜力，并增强非肌细胞向心肌细胞的分化。因此，内源性Smad 2激活是必不可少的内胚层和中胚层诱导的早期阶段。在晚期阶段，内源性转化生长因子-β通过Smad 2激活通过调节心肌细胞的增殖和分化来负调节心肌发生。
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.