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

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 cog...

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Autores principales: Wu, Xiaoyan, Dong, Wenhui, Zhang, Tianyi, Ren, Haozhen, Wang, Jinglin, Shang, Longcheng, Zhu, Zhengyi, Zhu, Wei, Shi, Xiaolei, Xu, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843934/
https://www.ncbi.nlm.nih.gov/pubmed/33520984
http://dx.doi.org/10.3389/fcell.2020.591246
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author Wu, Xiaoyan
Dong, Wenhui
Zhang, Tianyi
Ren, Haozhen
Wang, Jinglin
Shang, Longcheng
Zhu, Zhengyi
Zhu, Wei
Shi, Xiaolei
Xu, Yong
author_facet Wu, Xiaoyan
Dong, Wenhui
Zhang, Tianyi
Ren, Haozhen
Wang, Jinglin
Shang, Longcheng
Zhu, Zhengyi
Zhu, Wei
Shi, Xiaolei
Xu, Yong
author_sort Wu, Xiaoyan
collection PubMed
description 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.
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spelling pubmed-78439342021-01-30 Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation Wu, Xiaoyan Dong, Wenhui Zhang, Tianyi Ren, Haozhen Wang, Jinglin Shang, Longcheng Zhu, Zhengyi Zhu, Wei Shi, Xiaolei Xu, Yong Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2021-01-15 /pmc/articles/PMC7843934/ /pubmed/33520984 http://dx.doi.org/10.3389/fcell.2020.591246 Text en Copyright © 2021 Wu, Dong, Zhang, Ren, Wang, Shang, Zhu, Zhu, Shi and Xu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Wu, Xiaoyan
Dong, Wenhui
Zhang, Tianyi
Ren, Haozhen
Wang, Jinglin
Shang, Longcheng
Zhu, Zhengyi
Zhu, Wei
Shi, Xiaolei
Xu, Yong
Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation
title Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation
title_full Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation
title_fullStr Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation
title_full_unstemmed Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation
title_short Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation
title_sort epiregulin (ereg) and myocardin related transcription factor a (mrtf-a) form a feedforward loop to drive hepatic stellate cell activation
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843934/
https://www.ncbi.nlm.nih.gov/pubmed/33520984
http://dx.doi.org/10.3389/fcell.2020.591246
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