Ma Jin, van der Zon Gerard, Gonçalves Manuel A F V, van Dinther Maarten, Thorikay Midory, Sanchez-Duffhues Gonzalo, Ten Dijke Peter
Department of Cell Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
Oncode Institute, Leiden University Medical Center, Leiden, Netherlands.
Front Cell Dev Biol. 2021 Feb 12;9:616610. doi: 10.3389/fcell.2021.616610. eCollection 2021.
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 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 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 , , or 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.
内皮-间充质转化（EndMT）在胚胎发育和疾病进展中起重要作用。然而，转化生长因子-β（TGF-β）家族的不同成员如何调节EndMT尚不清楚。在本研究中，我们报道TGF-β2而非骨形态发生蛋白（BMP）9可在小鼠内皮MS-1和2H11细胞中触发EndMT。TGF-β2强烈上调转录因子SNAIL，敲低SNAIL足以消除TGF-β2触发的间充质样细胞形态获得和EndMT相关分子变化。虽然SLUG不受TGF-β2调节，但敲除SLUG也部分抑制2H11细胞中TGF-β2诱导的EndMT。有趣的是，除了SNAIL和SLUG，BMP9还刺激DNA结合抑制因子（ID）蛋白。抑制ID1、ID2或ID3的表达促进BMP9诱导EndMT，相反，异位表达ID1、ID2或ID3可消除TGF-β2介导的EndMT。总之，我们的结果表明SNAIL对TGF-β2介导的EndMT至关重要且不可或缺。虽然SLUG也参与EndMT过程，但它在其中的关键作用较小。相反，ID蛋白对于在EndMT过程中维持内皮特征和抑制SNAIL和SLUG的功能至关重要。这些数据表明，内皮细胞与间充质细胞状态的控制至少部分取决于SNAIL/SLUG和ID蛋白表达之间的平衡。
