YAP/TEAD3 signal mediates cardiac lineage commitment of human‐induced pluripotent stem cells

Abstract

Cardiomyocytes differentiated from human-induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo-YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo-YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage.Consistently, RNAi-based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP-TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo-YAP signal in cardiovascular lineage commitment. K E Y W O R D S cardiac differentiation, pluripotent stem cells, TEAD3, YAP

Context-dependent roles of YAP/TAZ in stem cell fates and cancer

“…Surprisingly, it has been recently shown that during reprogramming, cells that overexpress Yap1 promote the reprogramming of nearby somatic cells that are not overexpressing Yap1; indeed, cell-autonomous expression of Yap1 actually inhibits the acquisition of pluripotency [ 51 ]. Additionally, constitutive Yap1 expression promotes astrogenesis in neighboring cells during late embryonic development by upregulating Cntf and represses astrogenesis in a cell-autonomous manner [ 52 ]. Thus, whether a cell expresses Yap1 may not be as important as whether its neighbor expresses Yap1.…”

Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs

“…Upon binding of IL6 to IL6R, the homodimerization of gp130 is induced and a hexameric complex constituted of IL6/IL6R/gp130 is formed, which induce a signaling cascade through the JAK/STAT and SHP-2/ERK MAPK pathways regulating a variety of biological activities, including host defense 47 . TEAD3 codes for a member of transcriptional enhancer factor (TEF) family of transcription factors and plays roles in development, cell differentiation as well as proliferation 48,49 . LYN codes for a membrane-anchored src tyrosine kinase, localized on the cytoplasmic side of the plasma membrane and is an important regulator of signal transduction 50 .…”

Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal coronaviruses

“…Upon binding of IL6 to IL6R, the homodimerization of gp130 is induced and a hexameric complex constituted of IL6/IL6R/gp130 is formed, which induce a signaling cascade through the JAK/STAT and SHP-2/ERK MAPK pathways regulating a variety of biological activities, including host defense (Mihara et al, 2011). TEAD3 codes for a member of transcriptional enhancer factor (TEF) family of transcription factors and plays roles in development, cell differentiation as well as proliferation (Han et al, 2020; Imajo et al, 2015). LYN codes for a membrane-anchored src tyrosine kinase, localized on the cytoplasmic side of the plasma membrane and is an important regulator of signal transduction (Brodie et al, 2018).…”