Distinctive Roles of YAP and TAZ in Human Endothelial Progenitor Cells Growth and Functions.

Chanchao Lorthongpanich,Phatchanat Klaihmon,Surapol Issaragrisil,Sudjit Luanpitpong,Pakpoom Kheolamai

doi:10.3390/biomedicines10010147

Chanchao Lorthongpanich, Phatchanat Klaihmon + Show 3 more

Open Access

https://doi.org/10.3390/biomedicines10010147

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Abstract

The hippo signaling pathway plays an essential role in controlling organ size and balancing tissue homeostasis. Its two main effectors, yes-associated protein (YAP) and WW domain-containing transcription regulator 1, WWTR1 or TAZ, have also been shown to regulate endothelial cell functions and angiogenesis. In this study, the functions of YAP and TAZ in human endothelial progenitor cells (EPCs) were investigated by a loss-of-function study using CRISPR/Cas9-mediated gene knockdown (KD). Depletion of either YAP or TAZ reduced EPC survival and impaired many of their critical functions, including migration, invasion, vessel-formation, and expression of pro-angiogenic genes. Notably, TAZ-KD EPCs exhibited more severe phenotypes in comparison to YAP-KD EPCs. Moreover, the conditioned medium derived from TAZ-KD EPCs reduced the survivability of human lung cancer cells and increased their sensitivity to chemotherapeutic agents. The overexpression of either wild-type or constitutively active TAZ rescued the impaired phenotypes of TAZ-KD EPCs and restored the expression of pro-angiogenic genes in those EPCs. In summary, we demonstrate the crucial role of Hippo signaling components, YAP and TAZ, in controlling several aspects of EPC functions that can potentially be used as a drug target to enhance EPC functions in patients.

Highlights

In addition to mature endothelial cells that line the inner surface of the blood vessel wall, the bone marrow-derived circulating endothelial progenitor cells (EPCs), have been shown to play essential roles during postnatal tissue neovascularization under both physiological and pathological circumstances [1–3]
These results suggest that DH inhibits Hippo signaling in EPCs by increasing Yes-associated protein (YAP) phosphorylation and, by doing so, preventing its nuclear translocation
We investigated whether the reduction of YAP could result in the differential expression of endothelial genes, VEGFA, KDR, ANGPT2, and ANGPT1, in EPCs

Summary

Introduction

In addition to mature endothelial cells that line the inner surface of the blood vessel wall, the bone marrow-derived circulating endothelial progenitor cells (EPCs), have been shown to play essential roles during postnatal tissue neovascularization under both physiological and pathological circumstances [1–3]. Neovascularization requires several EPC functions, including their ability to mobilize from blood circulation into the target tissues before extensively proliferating, differentiating to mature endothelial cells, and generating new vascular structures [4]. EPCs help maintain vascular integrity by releasing numerous pro-angiogenic factors that enhance the survival and functions of normal endothelial cells [5]. The hippo signaling pathway is an evolutionarily conserved master regulator of several tissue functions, including cell proliferation, regulation of organ size, and, recently, vascular homeostasis and neovascularization. The hippo signaling pathway consists of a series of core kinases that regulate their downstream targets.

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