Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation.

Xiaoyan Wu,Jinglin Wang,Haozhen Ren,Longcheng Shang,Yong Xu,Wenhui Dong,Zhengyi Zhu,Xiaolei Shi,Tianyi Zhang,Wei Zhu

doi:10.3389/fcell.2020.591246

Abstract

Trans-differentiation of quiescent hepatic stellate cells (HSC) into myofibroblast cells is considered the linchpin of liver fibrosis. A myriad of signaling pathways contribute to HSC activation and consequently liver fibrosis. Epidermal growth factor (EGF) family of cytokines signal through the cognate receptor EGFR to promote HSC activation. In the present study we investigated the transcription regulation of epiregulin (EREG), an EGFR ligand, during HSC activation. We report that EREG expression was significantly up-regulated in activated HSCs compared to quiescent HSCs isolated from mice. In addition, there was an elevation of EREG expression in HSCs undergoing activation in vitro. Of interest, deficiency of myocardin-related transcription factor A (MRTF-A), a well-documented regulator of HSC trans-differentiation, attenuated up-regulation of EREG expression both in vivo and in vitro. Further analysis revealed that MRTF-A interacted with serum response factor (SRF) to bind directly to the EREG promoter and activate EREG transcription. EREG treatment promoted HSC activation in vitro, which was blocked by MRTF-A depletion or inhibition. Mechanistically, EREG stimulated nuclear trans-location of MRTF-A in HSCs. Together, our data portray an EREG-MRTF-A feedforward loop that contributes to HSC activation and suggest that targeting the EREG-MRTF-A axis may yield therapeutic solutions against liver fibrosis.

Highlights

Liver fibrosis is a key pathophysiological process taking place in response to various acute and chronic hepatic injuries (Lee et al, 2015)
It has been shown that amphiregulin (AR), an epidermal growth factor receptor (EGFR) ligand closely related to epiregulin (EREG), is activated during hepatic stellate cells (HSC) trans-differentiation and contributes to liver fibrosis (Perugorria et al, 2008)
In a third model of liver fibrosis in which the mice were subjected to the bile duct ligation (BDL) surgery (Figure 1I), picrosirius red staining showed significant liver fibrosis in the BDL mice compared to the sham-operated mice (Figure 1J). qPCR (Figure 1K) and Enzyme-Linked Immunosorbent Assay (ELISA) (Figure 1L) assays showed that EREG expression levels were up-regulated during HSC activation in vivo

Summary

Introduction

Liver fibrosis is a key pathophysiological process taking place in response to various acute and chronic hepatic injuries (Lee et al, 2015). Liver fibrosis can occur following the challenge of a myriad of injurious stimuli including pathogens, toxins, corrosive chemicals, and metabolites. Regardless of the specific triggering factor, myofibroblasts are considered the major effector cell type for liver fibrosis (Kisseleva, 2017). The origins from which myofibroblasts arise during liver fibrosis have been a subject matter receiving extensive investigations. Lineage fate-mapping experiments have been determined that an overwhelming majority (>90%) of myofibroblasts in the liver are derived from hepatic stellate cells (HSC) that express lecithin retinol acyltransferase (Lrat), a supposedly HSC lineage-specific marker gene (Mederacke et al, 2013). In vitro cultured HSCs can be educated to switch to a myofibroblast-like phenotype by a host of growth factors including transforming growth factor (TGF-β) and platelet-derived growth factor (PDGF) (Hou and Syn, 2018)

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Results

Conclusion