Endothelial-to-mesenchymal transition (EndMT) plays an important role in embryonic development and disease progression. Yet, how different members of the transforming growth factor-beta (TGF-beta)... Show moreEndothelial-to-mesenchymal transition (EndMT) plays an important role in embryonic development and disease progression. Yet, how different members of the transforming growth factor-beta (TGF-beta) family regulate EndMT is not well understood. In the current study, we report that TGF-beta 2, but not bone morphogenetic protein (BMP)9, triggers EndMT in murine endothelial MS-1 and 2H11 cells. TGF-beta 2 strongly upregulates the transcription factor SNAIL, and the depletion of Snail is sufficient to abrogate TGF-beta 2-triggered mesenchymal-like cell morphology acquisition and EndMT-related molecular changes. Although SLUG is not regulated by TGF-beta 2, knocking out Slug also partly inhibits TGF-beta 2-induced EndMT in 2H11 cells. Interestingly, in addition to SNAIL and SLUG, BMP9 stimulates inhibitor of DNA binding (ID) proteins. The suppression of Id1, Id2, or Id3 expression facilitated BMP9 in inducing EndMT and, in contrast, ectopic expression of ID1, ID2, or ID3 abrogated TGF-beta 2-mediated EndMT. Altogether, our results show that SNAIL is critical and indispensable for TGF-beta 2-mediated EndMT. Although SLUG is also involved in the EndMT process, it plays less of a crucial role in it. In contrast, ID proteins are essential for maintaining endothelial traits and repressing the function of SNAIL and SLUG during the EndMT process. These data suggest that the control over endothelial vs. mesenchymal cell states is determined, at least in part, by a balance between the expression of SNAIL/SLUG and ID proteins. Show less
Ma, J.; Sanchez Duffhues, G.; Goumans, M.J.; Dijke, P. ten 2020
Endothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system... Show moreEndothelial to mesenchymal transition (EndMT) is a complex biological process that gives rise to cells with multipotent potential. EndMT is essential for the formation of the cardiovascular system during embryonic development. Emerging results link EndMT to the postnatal onset and progression of fibrotic diseases and cancer. Moreover, recent reports have emphasized the potential for EndMT in tissue engineering and regenerative applications by regulating the differentiation status of cells. Transforming growth factor beta (TGF-beta) engages in many important physiological processes and is a potent inducer of EndMT. In this review, we first summarize the mechanisms of the TGF-beta signaling pathway as it relates to EndMT. Thereafter, we discuss the pivotal role of TGF-beta-induced EndMT in the development of cardiovascular diseases, fibrosis, and cancer, as well as the potential application of TGF-beta-induced EndMT in tissue engineering. Show less
Sanchez Duffhues, G.; Vinuesa, A.G. de; Dijke, P. ten 2018
