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

Abstract

Background & AimsLiver 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.MethodsEng expression was measured in human and murine samples of liver injury. After generating GFAPCre(+)EngΔ HSC mice, the impact of Endoglin deletion on chronic liver fibrosis was analysed. For in vitro analysis, Engflox/flox HSCs were infected with Cre‐expressing virus to deplete Endoglin and fibrogenic responses were analysed.ResultsEndoglin 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 GFAPC re(−)Engf/f to GFAPC re(+)EngΔ HSC mice in toxic liver injury, livers of GFAPC re(+)EngΔ HSC mice showed 39.9% (P < .01) higher Hydroxyproline content compared to GFAPC re(−)Engf/f littermates. Sirius Red staining underlined these findings, showing 58.8% (P < .05) more Collagen deposition in livers of GFAPC re(+)EngΔ HSC mice. Similar results were obtained in mice subjected to cholestatic injury.ConclusionEndoglin 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.

Endoglin: Beyond the Endothelium

“…Other studies, on the other hand, show that endoglin might also be protective during fibrosis. In a murine model for liver fibrosis, endoglin deficiency enhanced the expression of pro-fibrotic factors such as α-SMA and fibronectin [118]. The authors suggest that endoglin might work protectively by modulating ALK1-versus ALK5-dependent TGF-β signaling.…”

Application Value of Magnetic Resonance Perfusion Imaging in the Early Diagnosis of Rat Hepatic Fibrosis

“…Hepatic stellate cells (HSCs) are the main source of collagen and ECM [2]. After liver injury, resting HSCs are transformed into activated myofibroblasts, followed by ECM synthesis [3]. When the synthesis of ECM is greater than consumption, hepatic fibrosis develops gradually, leading to liver dysfunction, portal hypertension, and hepatocellular carcinoma (HCC) [1,4].…”

Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy

“…In humans, endoglin is expressed in the liver with a much higher abundance of the L-ENG splice variant [13]. The research on the murine model has shown that S-ENG is an anti-angiogenic molecule, in contrast to the pro-angiogenic activity of L-endoglin [77].…”

“…The commonly suggested role of CD105 in carcinogenesis is based on clinical studies, as well as in vitro and animal model experiments. The results of said research indicate the potential role of CD105 in liver fibrosis [11,12,13] and hepatocellular carcinoma progression [12,14,15,16,17,18,19,20,21,22]. However, the observations concerning quantitative endoglin expression and its prognostic role in HCC are not coherent.…”

“…However, none of them focused on HCC in particular [23]. The molecular mechanisms of HCC involving endoglin described in the literature connect this marker with both tumour angiogenesis [4,5] and liver fibrosis [11,12,13], while the autocrine/paracrine mechanisms of action of endoglin, produced by tumour cells, are poorly recognized [23,24].…”