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Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis

BACKGROUND & AIMS: Liver fibrosis is the outcome of chronic liver injury. Transforming growth factor‐β (TGF‐β) is a major profibrogenic cytokine modulating hepatic stellate cell (HSC) activation and extracellular matrix homeostasis. This study analyses the effect of Endoglin (Eng), a TGF‐β type...

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Autores principales: Alsamman, Muhammad, Sterzer, Viktor, Meurer, Steffen K., Sahin, Hacer, Schaeper, Ute, Kuscuoglu, Deniz, Strnad, Pavel, Weiskirchen, Ralf, Trautwein, Christian, Scholten, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947658/
https://www.ncbi.nlm.nih.gov/pubmed/28941022
http://dx.doi.org/10.1111/liv.13595
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author Alsamman, Muhammad
Sterzer, Viktor
Meurer, Steffen K.
Sahin, Hacer
Schaeper, Ute
Kuscuoglu, Deniz
Strnad, Pavel
Weiskirchen, Ralf
Trautwein, Christian
Scholten, David
author_facet Alsamman, Muhammad
Sterzer, Viktor
Meurer, Steffen K.
Sahin, Hacer
Schaeper, Ute
Kuscuoglu, Deniz
Strnad, Pavel
Weiskirchen, Ralf
Trautwein, Christian
Scholten, David
author_sort Alsamman, Muhammad
collection PubMed
description BACKGROUND & AIMS: Liver fibrosis is the outcome of chronic liver injury. Transforming growth factor‐β (TGF‐β) is a major profibrogenic cytokine modulating hepatic stellate cell (HSC) activation and extracellular matrix homeostasis. This study analyses the effect of Endoglin (Eng), a TGF‐β type III auxiliary receptor, on fibrogenesis in two models of liver injury by HSC‐specific endoglin deletion. METHODS: Eng expression was measured in human and murine samples of liver injury. After generating GFAP(Cre(+))Eng(Δ) (HSC) mice, the impact of Endoglin deletion on chronic liver fibrosis was analysed. For in vitro analysis, Eng(flox/flox) HSCs were infected with Cre‐expressing virus to deplete Endoglin and fibrogenic responses were analysed. RESULTS: Endoglin is upregulated in human liver injury. The receptor is expressed in liver tissues and mesenchymal liver cells with much higher abundance of the L‐Eng splice variant. Comparing GFAP(C) (re(−))Eng(f/f) to GFAP(C) (re(+))Eng(Δ) (HSC) mice in toxic liver injury, livers of GFAP(C) (re(+))Eng(Δ) (HSC) mice showed 39.9% (P < .01) higher Hydroxyproline content compared to GFAP(C) (re(−))Eng(f/f) littermates. Sirius Red staining underlined these findings, showing 58.8% (P < .05) more Collagen deposition in livers of GFAP(C) (re(+))Eng(Δ) (HSC) mice. Similar results were obtained in mice subjected to cholestatic injury. CONCLUSION: Endoglin isoforms are differentially upregulated in liver samples of patients with chronic and acute liver injury. Endoglin deficiency in HSC significantly aggravates fibrosis in response to injury in two different murine models of liver fibrosis and increases α‐SMA and fibronectin expression in vitro. This suggests that Endoglin protects against fibrotic injury, likely through modulation of TGF‐β signalling.
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spelling pubmed-59476582018-05-17 Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis Alsamman, Muhammad Sterzer, Viktor Meurer, Steffen K. Sahin, Hacer Schaeper, Ute Kuscuoglu, Deniz Strnad, Pavel Weiskirchen, Ralf Trautwein, Christian Scholten, David Liver Int Cirrhosis and Liver Failure BACKGROUND & AIMS: Liver fibrosis is the outcome of chronic liver injury. Transforming growth factor‐β (TGF‐β) is a major profibrogenic cytokine modulating hepatic stellate cell (HSC) activation and extracellular matrix homeostasis. This study analyses the effect of Endoglin (Eng), a TGF‐β type III auxiliary receptor, on fibrogenesis in two models of liver injury by HSC‐specific endoglin deletion. METHODS: Eng expression was measured in human and murine samples of liver injury. After generating GFAP(Cre(+))Eng(Δ) (HSC) mice, the impact of Endoglin deletion on chronic liver fibrosis was analysed. For in vitro analysis, Eng(flox/flox) HSCs were infected with Cre‐expressing virus to deplete Endoglin and fibrogenic responses were analysed. RESULTS: Endoglin is upregulated in human liver injury. The receptor is expressed in liver tissues and mesenchymal liver cells with much higher abundance of the L‐Eng splice variant. Comparing GFAP(C) (re(−))Eng(f/f) to GFAP(C) (re(+))Eng(Δ) (HSC) mice in toxic liver injury, livers of GFAP(C) (re(+))Eng(Δ) (HSC) mice showed 39.9% (P < .01) higher Hydroxyproline content compared to GFAP(C) (re(−))Eng(f/f) littermates. Sirius Red staining underlined these findings, showing 58.8% (P < .05) more Collagen deposition in livers of GFAP(C) (re(+))Eng(Δ) (HSC) mice. Similar results were obtained in mice subjected to cholestatic injury. CONCLUSION: Endoglin isoforms are differentially upregulated in liver samples of patients with chronic and acute liver injury. Endoglin deficiency in HSC significantly aggravates fibrosis in response to injury in two different murine models of liver fibrosis and increases α‐SMA and fibronectin expression in vitro. This suggests that Endoglin protects against fibrotic injury, likely through modulation of TGF‐β signalling. John Wiley and Sons Inc. 2017-10-23 2018-05 /pmc/articles/PMC5947658/ /pubmed/28941022 http://dx.doi.org/10.1111/liv.13595 Text en © 2017 The Authors Liver International Published by John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Cirrhosis and Liver Failure
Alsamman, Muhammad
Sterzer, Viktor
Meurer, Steffen K.
Sahin, Hacer
Schaeper, Ute
Kuscuoglu, Deniz
Strnad, Pavel
Weiskirchen, Ralf
Trautwein, Christian
Scholten, David
Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis
title Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis
title_full Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis
title_fullStr Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis
title_full_unstemmed Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis
title_short Endoglin in human liver disease and murine models of liver fibrosis—A protective factor against liver fibrosis
title_sort endoglin in human liver disease and murine models of liver fibrosis—a protective factor against liver fibrosis
topic Cirrhosis and Liver Failure
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947658/
https://www.ncbi.nlm.nih.gov/pubmed/28941022
http://dx.doi.org/10.1111/liv.13595
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