3 years ago

Endoglin in human liver disease and murine models of liver fibrosis – a protective factor against liver fibrosis

Ralf Weiskirchen, Ute Schäper, Christian Trautwein, Hacer Sahin, David Scholten, Pavel Strnad, Muhammad Alsamman, Viktor Sterzer, Deniz Kuscuoglu, Steffen Klaus Meurer
Background & aims Liver fibrosis is the outcome of chronic liver injury. TGF-β is a major profibrogenic cytokine modulating hepatic stellate cell (HSC) activation and extracellular matrix homeostasis. This study analyzes 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 GFAPCre(+)EngΔHSC mice the impact of Endoglin deletion on chronic liver fibrosis was analyzed. For in vitro analysis, Engflox/flox HSCs were infected with Cre expressing virus to deplete Endoglin and fibrogenic responses were analyzed. Results Eng 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 GFAPCre(-)Engf/f to GFAPCre(+)EngΔHSC mice in toxic liver injury, livers of GFAPCre(+)EngΔHSC mice showed 39.9% (p<0.01) higher Hydroxyproline content compared to GFAPCre(-)Engf/f littermates. Sirius Red staining underlined these findings, showing 58.8% (p<0.05) more Collagen deposition in livers of GFAPCre(+)EngΔHSC mice. Similar results were obtained in mice subjected to cholestatic injury. Conclusion Endoglin isoforms are differentially up-regulated 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 signaling. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/liv.13595

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