2. Academic Validation
  3. VGLL4-TEAD1 promotes vascular smooth muscle cell differentiation from human pluripotent stem cells via TET2

VGLL4-TEAD1 promotes vascular smooth muscle cell differentiation from human pluripotent stem cells via TET2

  • J Mol Cell Cardiol. 2023 Jan 16;176:21-32. doi: 10.1016/j.yjmcc.2023.01.005.
Zuxuan Wang 1,  Yingyi Quan 1,  Minjie Hu 1,  Yubin Xu 1,  Yuhao Chen 1,  Peifeng Jin 2,  Jianshe Ma 1,  Xiufang Chen 3,  Junming Fan 1,  Xiaofang Fan 1,  Yongsheng Gong 1,  Ming Li 3,  Yongyu Wang 4
Affiliations

Affiliations

  • 1 Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
  • 2 Department of Cardiothoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
  • 3 Cardiac Regeneration Research Institute, School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325015, Zhejiang, China.
  • 4 Institute of Hypoxia Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325015, Zhejiang, China; Cardiac Regeneration Research Institute, School of Basic Medical Science, Wenzhou Medical University, Wenzhou 325015, Zhejiang, China. Electronic address: [email protected].
PMID: 36657637 DOI: 10.1016/j.yjmcc.2023.01.005
Abstract

The Hippo signaling pathway plays a critical role in cardiovascular development and stem cell differentiation. Using microarray profiling, we found that the Hippo pathway components vestigial-like family member 4 (VGLL4) and TEA domain transcription factor 1 (TEAD1) were upregulated during vascular smooth muscle cell (VSMC) differentiation from H1 ESCs (H1 embryonic stem cells). To further explore the role and molecular mechanisms of VGLL4 in regulating VSMC differentiation, we generated a VGLL4-knockdown H1 ESC line (heterozygous knockout) using the CRISPR/Cas9 system and found that VGLL4 knockdown inhibited VSMC specification. In contrast, overexpression of VGLL4 using the PiggyBac transposon system facilitated VSMC differentiation. We confirmed that this effect was mediated via TEAD1 and VGLL4 interaction. In addition, bioinformatics analysis revealed that Ten-eleven-translocation 2 (TET2), a DNA dioxygenase, is a target of TEAD1, and a luciferase assay further verified that TET2 is the target of the VGLL4-TEAD1 complex. Indeed, TET2 overexpression promoted VSMC marker gene expression and countered the VGLL4 knockdown-mediated inhibitory effects on VSMC differentiation. In summary, we revealed a novel role of VGLL4 in promoting VSMC differentiation from hESCs and identified TET2 as a new target of the VGLL4-TEAD1 complex, which may demethylate VSMC marker genes and facilitate VSMC differentiation. This study provides new insights into the VGLL4-TEAD1-TET2 axis in VSMC differentiation and vascular development.

Keywords

Cell differentiation; Pluripotent stem cells; TEA domain transcription factor 1 (TEAD1); Ten-eleven-translocation 2 (TET2); Vascular smooth muscle cell; Vestigial-like family member 4 (VGLL4).

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