Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells
Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells
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DOI：
10.1242/jcs.028282
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发表时间：
2008-10-15
影响因子：
4
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Kokudo, Takashi;Suzuki, Yuka;Miyazono, Kohei
上皮间质转化（Epithelial-mesenchymal transition，EMT）在多种生理和病理过程中发挥重要作用，并受到转化生长因子β（transforming growth factor beta，TGF β）等细胞因子介导的信号通路的调控。胚胎内皮细胞在心脏瓣膜形成和主动脉成熟期间也经历分化成间充质细胞。然而，调节这种内皮间质转化（EndMT）的分子机制仍有待阐明。在这里，我们表明，TGF β在小鼠胚胎干细胞衍生的内皮细胞（MESECs）的壁分化过程中起着重要作用。TGF β 2诱导MESEC分化为壁细胞，内皮标志物claudin 5的表达减少，壁标志物平滑肌α-肌动蛋白、SM 22 α和钙调蛋白的表达增加，而TGF β I型受体激酶抑制剂抑制EndMT。在参与EMT的转录因子中，Snail在MESEC中被TGF β 2诱导。四环素调控的Snail表达诱导MESEC分化为壁细胞，而Snail表达的敲低废除了TGF β 2诱导的MESEC的壁分化。这些结果表明Snail介导诱导EndMT的内源性TGF β信号的作用。
Epithelial-mesenchymal transition (EMT) plays important roles in various physiological and pathological processes, and is regulated by signaling pathways mediated by cytokines, including transforming growth factor beta (TGF beta). Embryonic endothelial cells also undergo differentiation into mesenchymal cells during heart valve formation and aortic maturation. However, the molecular mechanisms that regulate such endothelial-mesenchymal transition (EndMT) remain to be elucidated. Here we show that TGF beta plays important roles during mural differentiation of mouse embryonic stem cell-derived endothelial cells ( MESECs). TGF beta 2 induced the differentiation of MESECs into mural cells, with a decrease in the expression of the endothelial marker claudin 5, and an increase in expression of the mural markers smooth muscle alpha-actin, SM22 alpha and calponin, whereas a TGF beta type I receptor kinase inhibitor inhibited EndMT. Among the transcription factors involved in EMT, Snail was induced by TGF beta 2 in MESECs. Tetracycline-regulated expression of Snail induced the differentiation of MESECs into mural cells, whereas knockdown of Snail expression abrogated TGF beta 2-induced mural differentiation of MESECs. These results indicate that Snail mediates the actions of endogenous TGF beta signals that induce EndMT.