Transcription Factor 4 Maintains Endothelial Cell Identity by Inhibiting Endothelial to Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndoMT) is essential for embryonic heart development and contributes to many disease-causal pathobiological processes. It is unclear how the balance between endothelial cell (EC) identity and EndoMT mediators is regulated to drive this transition. This study identifies TCF4 as a critical EC identity gene. TCF4 knockdown in ECs impairs EC phenotype and function, and induces EC identity transition towards mesenchymal-like state. This discovery suggests that TCF4 functions as a guardian of EC identity against EndoMT. Mechanistically, TCF4 binds directly to the promoter of TGFB1 and SNAI1, leading to the repression of their expression. TCF4 expression is consistently downregulated in three EndoMT models. TCF4 downregulation diminishes its inhibitory effect on the TGFB signaling pathway, leading to upregulation of SNAI1 and TGFB1, and subsequently enhancing EndoMT. This, in turn, further suppresses TCF4 expression. Consequently, the TCF4-TGFB1 feedback loop is formed to intensify the EndoMT process. We demonstrate that introducing exogenous TCF4 disrupts this TCF4-TGFB1 feedback loop of EndoMT, rescuing EC phenotype and function under TGFB1 stimulation, as well as ECs from heart failure patients. Our results reveal a key role of TCF4 in safeguarding EC identity and preventing EndoMT, suggesting a therapeutic potential of TCF4 for EndoMT-related cardiovascular diseases.