TGF-β-Induced Endothelial to Mesenchymal Transition Is Determined by a Balance Between SNAIL and ID Factors.

Jin Ma,Gerard Van Der Zon,Maarten Van Dinther,Manuel A F V Gonçalves,Peter Ten Dijke,Midory Thorikay,Gonzalo Sanchez-Duffhues

doi:10.3389/fcell.2021.616610

Abstract

Endothelial-to-mesenchymal transition (EndMT) plays an important role in embryonic development and disease progression. Yet, how different members of the transforming growth factor-β (TGF-β) family regulate EndMT is not well understood. In the current study, we report that TGF-β2, but not bone morphogenetic protein (BMP)9, triggers EndMT in murine endothelial MS-1 and 2H11 cells. TGF-β2 strongly upregulates the transcription factor SNAIL, and the depletion of Snail is sufficient to abrogate TGF-β2-triggered mesenchymal-like cell morphology acquisition and EndMT-related molecular changes. Although SLUG is not regulated by TGF-β2, knocking out Slug also partly inhibits TGF-β2-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-β2-mediated EndMT. Altogether, our results show that SNAIL is critical and indispensable for TGF-β2-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.

Highlights

In diverse physiological and pathological processes, endothelial cells show remarkable plasticity as they lose endothelial properties and differentiate into mesenchymal cells, a process termed endothelial-to-mesenchymal transition (EndMT) (Dejana and Lampugnani, 2018)
We investigated whether the transforming growth factor-β (TGF-β) family ligands TGF-β2 and BMP9 are capable of inducing EndMT in two murine endothelial cell lines, i.e., pancreatic microvascular endothelial cells (MS-1) and lymphatic endothelial cells (2H11)
We report that TGF-β2 triggers EndMT in two murine endothelial cell lines, i.e., MS-1 and 2H11

Summary

Introduction

In diverse physiological and pathological processes, endothelial cells show remarkable plasticity as they lose endothelial properties and differentiate into mesenchymal cells, a process termed endothelial-to-mesenchymal transition (EndMT) (Dejana and Lampugnani, 2018). EndMT is a gradual and reversible dynamic process, which shares similarities with epithelial-to-mesenchymal transition (EMT) (Saito, 2013). Epithelial cells can acquire different EMT features with mixed epithelial/mesenchymal phenotype. This has recently been described as epithelial cell plasticity (Yang et al, 2020). When cobblestone-shaped endothelial cells (ECs) undergo EndMT, they gradually lose their tight junctions and acquire a mesenchymal-like identity and the appearance of elongated fibroblasts. To allow for clinical translation of EndMT modulating approaches, more insights into the underlying molecular and cellular mechanisms of EndMT are needed

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