VGLL4 promotes vascular endothelium specification via TEAD1 in the vascular organoids and human pluripotent stem cells-derived endothelium model

• Published in: Cellular and molecular life sciences : CMLS 2023-08, Vol.80 (8), p.215-215, Article 215
• Main Authors: Quan, Yingyi, Hu, Minjie, Jiang, Jiang, Jin, Peifeng, Fan, Junming, Li, Ming, Fan, Xiaofang, Gong, Yongsheng, Yang, Yang, Wang, Yongyu
• Format: Article
• Language: English
• Subjects: Biochemistry; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Differentiation; Differentiation (biology); Ectopic expression; Embryo cells; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Endothelium, Vascular - metabolism; Gene Expression Regulation; Humans; Immunoprecipitation; Life Sciences; Organoids; Original; Original Article; Pluripotency; Pluripotent Stem Cells - metabolism; Signal transduction; Specifications; Stem cells; TEA Domain Transcription Factors; Transcription factors; Transcription Factors - metabolism; Yes-associated protein
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-023-04858-w

Background We have shown that Hippo-YAP signaling pathway plays an important role in endothelial cell differentiation. Vestigial-like family member 4 (VGLL4) has been identified as a YAP inhibitor. However, the exact function of VGLL4 in vascular endothelial cell development remains unclear. In this study, we investigated the role of VGLL4, in human endothelial lineage specification both in 3D vascular organoid and 2D endothelial cell differentiation. Methods and results In this study, we found that VGLL4 was increased during 3D vascular organoids generation and directed differentiation of human embryonic stem cells H1 towards the endothelial lineage. Using inducible ectopic expression of VGLL4 based on the piggyBac system, we proved that overexpression of VGLL4 in H1 promoted vascular organoids generation and endothelial cells differentiation. In contrast, VGLL4 knockdown (heterozygous knockout) of H1 exhibited inhibitory effects. Using bioinformatics analysis and protein immunoprecipitation, we further found that VGLL4 binds to TEAD1 and facilitates the expression of endothelial master transcription factors, including FLI1 , to promote endothelial lineage specification. Moreover, TEAD1 overexpression rescued VGLL4 knockdown-mediated negative effects. Conclusions In summary, VGLL4 promotes EC lineage specification both in 3D vascular organoid and 2D EC differentiation from pluripotent stem cell, VGLL4 interacts with TEAD1 and facilitates EC key transcription factor, including FLI1 , to enhance EC lineage specification.