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First published online 16 September 2008
doi: 10.1242/jcs.028282

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Snail is required for TGFβ-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells

Department of Molecular Pathology, Graduate School of Medicine and the Global Center of Excellence Program for `Integrative Life Science Based on the Study of Biosignaling Mechanisms', The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

^* Author for correspondence (e-mail: t-watabe{at}umin.ac.jp)

Accepted 16 July 2008

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 β (TGFβ). 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 TGFβ plays important roles during mural differentiation of mouse embryonic stem cell-derived endothelial cells (MESECs). TGFβ2 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 -actin, SM22 and calponin, whereas a TGFβ type I receptor kinase inhibitor inhibited EndMT. Among the transcription factors involved in EMT, Snail was induced by TGFβ2 in MESECs. Tetracycline-regulated expression of Snail induced the differentiation of MESECs into mural cells, whereas knockdown of Snail expression abrogated TGFβ2-induced mural differentiation of MESECs. These results indicate that Snail mediates the actions of endogenous TGFβ signals that induce EndMT.

Key words: TGFβ2, TβR-I inhibitor, Snail, EMT, EndMT, Embryonic stem cell, Claudin 5, Smooth muscle -actin

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