Endoglin in human liver disease and murine models of liver fibrosis-A protective factor against liver fibrosis
Endoglin in human liver disease and murine models of liver fibrosis-A protective factor against liver fibrosis
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DOI：
10.1111/liv.13595
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发表时间：
2018-05-01
影响因子：
6.7
通讯作者：
Scholten, David
中科院分区：
文献类型：
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作者：
Alsamman, Muhammad;Sterzer, Viktor;Scholten, David
背景与目的：肝纤维化是慢性肝损伤的结果。转化生长因子-β (TGF-β) 是一种主要的促纤维化细胞因子，调节肝星状细胞 (HSC) 活化和细胞外基质稳态。本研究分析了内皮糖蛋白 (Eng)（一种 TGF-β III 型辅助受体）对 HSC 特异性内皮糖蛋白缺失的两种肝损伤模型中纤维形成的影响。方法：在人类和小鼠肝损伤样本中测量 Eng 表达。生成GFAP(Cre(+)) Eng(Delta HSC)小鼠后，分析Endoglin缺失对慢性肝纤维化的影响。对于体外分析，Eng(flox/flox) HSCs 用表达 Cre 的病毒感染以消耗 Endoglin，并分析纤维化反应。结果：Endoglin 在人类肝损伤中上调。该受体在肝组织和间充质肝细胞中表达，L-Eng 剪接变体的丰度要高得多。比较中毒性肝损伤中的 GFAP(Cre(-)) Eng(f/f) 与 GFAP(Cre(+)) Eng(Delta HSC) 小鼠，与 GFAP(Cre(-)) Eng(f/f) 同窝小鼠相比，GFAP(Cre(+)) Eng(Delta HSC) 小鼠的肝脏羟脯氨酸含量高出 39.9% (P < .01)。天狼星红染色强调了这些发现，显示 GFAP(Cre(+)) Eng(Delta HSC) 小鼠肝脏中的胶原蛋白沉积增加了 58.8% (P < .05)。在遭受胆汁淤积损伤的小鼠中也获得了类似的结果。结论：慢性和急性肝损伤患者的肝脏样本中内皮糖蛋白亚型存在差异性上调。在两种不同的肝纤维化小鼠模型中，HSC 中的内皮糖蛋白缺陷显着加剧了损伤后的纤维化，并增加了体外 α-SMA 和纤连蛋白的表达。这表明内皮糖蛋白可能通过调节 TGF-β 信号传导来防止纤维化损伤。
Background & Aims: Liver fibrosis is the outcome of chronic liver injury. Transforming growth factor-beta (TGF-beta) 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-beta 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(Delta 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(Cre(-)) Eng(f/f) to GFAP(Cre(+)) Eng(Delta HSC) mice in toxic liver injury, livers of GFAP(Cre(+)) Eng(Delta HSC) mice showed 39.9% (P < .01) higher Hydroxyproline content compared to GFAP(Cre(-)) Eng(f/f) littermates. Sirius Red staining underlined these findings, showing 58.8% (P < .05) more Collagen deposition in livers of GFAP(Cre(+)) Eng(Delta 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 alpha-SMA and fibronectin expression in vitro. This suggests that Endoglin protects against fibrotic injury, likely through modulation of TGF-beta signalling.