# Transcription factor 4 maintains endothelial cell identity by inhibiting endothelial to mesenchymal transition

## TL;DR

This paper shows that TCF4 prevents endothelial cells from turning into mesenchymal cells, which is important for heart development and disease.

## Contribution

The study identifies TCF4 as a novel regulator of endothelial cell identity by inhibiting EndoMT through a TCF4–TGFβ feedback loop.

## Key findings

- TCF4 knockdown leads to endothelial to mesenchymal transition and loss of endothelial cell function.
- TCF4 represses TGFβ signaling pathway genes by binding to their promoters.
- Exogenous TCF4 disrupts the TCF4–TGFβ feedback loop and rescues endothelial cell identity in heart failure patients.

## Abstract

Endothelial to mesenchymal transition (EndoMT) is essential for embryonic heart development and contributes to many pathological processes. It is unclear how the balance between endothelial cell (EC) identity and EndoMT mediators is regulated to drive this transition. This study identifies transcription factor 4 (TCF4; also known as ITF2) as a critical EC identity gene. TCF4 knockdown impairs EC phenotype and function, and induces a transition towards a mesenchymal-like state. This discovery suggests that TCF4 safeguards EC identity against EndoMT. Mechanistically, TCF4 directly binds to the promoter of multiple key genes in the transforming growth factor-β (TGFβ) signaling pathway, thereby repressing their expression. TCF4 expression is consistently down-regulated in three EndoMT models. TCF4 down-regulation diminishes its inhibitory effect on the TGFβ signaling pathway, leading to pathway activation and subsequently enhancing EndoMT. This, in turn, further suppresses TCF4 expression. Consequently, the TCF4–TGFβ feedback loop is formed to intensify the EndoMT process. We demonstrate that introducing exogenous TCF4 disrupts this TCF4–TGFβ feedback loop of EndoMT, rescuing the EC phenotype and function under TGFβ stimulation, as well as ECs from human patients with heart failure. Our results reveal a key role for TCF4 in safeguarding EC identity and preventing EndoMT, suggesting a therapeutic potential of targeting TCF4 for EndoMT-related cardiovascular diseases.

Graphical Abstract