Snail is required for TGFbeta-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells.
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 (TGFbeta). 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 TGFbeta plays important roles during mural differentiation of mouse embryonic stem cell-derived endothelial cells (MESECs). TGFbeta2 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, SM22alpha and calponin, whereas a TGFbeta type I receptor kinase inhibitor inhibited EndMT. Among the transcription factors involved in EMT, Snail was induced by TGFbeta2 in MESECs. Tetracycline-regulated expression of Snail induced the differentiation of MESECs into mural cells, whereas knockdown of Snail expression abrogated TGFbeta2-induced mural differentiation of MESECs. These results indicate that Snail mediates the actions of endogenous TGFbeta signals that induce EndMT.
Kokudo
Takashi
T
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.
Suzuki
Yuka
Y
Yoshimatsu
Yasuhiro
Y
Yamazaki
Tomoko
T
Watabe
Tetsuro
T
Miyazono
Kohei
K
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001011:Aorta / Q000166:cytology / Q000196:embryology; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D062507:Claudin-5; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006351:Heart Valves / Q000166:cytology / Q000196:embryology; D008565:Membrane Proteins / Q000096:biosynthesis; D008648:Mesoderm / Q000166:cytology / Q000196:embryology*; D051379:Mice; D008840:Microfilament Proteins / Q000096:biosynthesis; D009124:Muscle Proteins / Q000096:biosynthesis; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism* / Q000494:pharmacology; D000096985:Calponins
D000943:Antigens, Differentiation; D002135:Calcium-Binding Proteins; D062507:Claudin-5; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D018125:Receptors, Transforming Growth Factor beta; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2; D000096985:Calponins; C491511:Cldn5 protein, mouse; C051615:transgelin