Division of Liver Diseases, Department of Medicine, Ichan School of Medicine at Mount Sinai, New York, New York, USA.
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Gut. 2014 Nov;63(11):1805-18. doi: 10.1136/gutjnl-2013-306373. Epub 2014 Feb 4.
In human chronic liver disease, there is association between ductular reaction (DR) and fibrosis; yet, the mechanism triggering its onset and its role in scar formation remains unknown. Since we previously showed that osteopontin (OPN) is highly induced during drug-induced liver fibrosis, we hypothesised that OPN could drive oval cells (OC) expansion and DR and signal to hepatic stellate cells (HSC) to promote scarring.
In vivo studies demonstrated increased OPN expression in biliary epithelial cells (BEC) and in OC in thioacetamide (TAA)-treated mice. OPN ablation protected mice from TAA and bile duct ligation-induced liver injury, DR and scarring. This was associated with greater hepatocyte proliferation, lower OC expansion and DR along with less fibrosis, suggesting that OPN could activate the OC compartment to differentiate into BEC, which could then signal to HSC to enhance scarring. Since TAA-treated wild-type mice and cirrhotic patients showed TGF-β(+) BEC, which were lacking in TAA-treated Opn(-/-) mice and in healthy human explants, this suggested that OPN could regulate TGF-β, a profibrogenic factor. In vitro experiments confirmed that recombinant OPN (rOPN) decreases hepatocyte proliferation and increases OC and BEC proliferation. To evaluate how BEC regulate collagen-I production in HSC, co-cultures were established. Co-cultured BEC upregulated OPN and TGF-β expression and enhanced collagen-I synthesis by HSC. Lastly, recombinant TGF-β (rTGFβ) and rOPN promoted BEC proliferation and neutralisation of OPN and TGF-β reduced collagen-I expression in co-cultured HSC.
OPN emerges as a key matricellular protein driving DR and contributing to scarring and liver fibrosis via TGF-β.
在人类慢性肝病中，胆管反应（DR）与纤维化之间存在关联；然而，触发其发生的机制及其在瘢痕形成中的作用尚不清楚。由于我们之前表明骨桥蛋白（OPN）在药物诱导的肝纤维化过程中高度诱导，我们假设 OPN 可以驱动卵圆细胞（OC）扩增和 DR，并向肝星状细胞（HSC）发出信号以促进瘢痕形成。
体内研究表明，硫代乙酰胺（TAA）处理的小鼠中胆管上皮细胞（BEC）和 OC 中 OPN 表达增加。OPN 缺失可保护小鼠免受 TAA 和胆管结扎诱导的肝损伤、DR 和瘢痕形成。这与更高的肝细胞增殖、更少的 OC 扩增和 DR 以及更少的纤维化有关，表明 OPN 可以激活 OC 区室分化为 BEC，然后向 HSC 发出信号以增强瘢痕形成。由于 TAA 处理的野生型小鼠和肝硬化患者显示 TGF-β（+）BEC，而 TAA 处理的 Opn（-/-）小鼠和健康人外植体中缺乏 TGF-β（+）BEC，这表明 OPN 可以调节 TGF-β，一种促纤维化因子。体外实验证实重组 OPN（rOPN）可降低肝细胞增殖并增加 OC 和 BEC 增殖。为了评估 BEC 如何调节 HSC 中胶原-I 的产生，建立了共培养物。共培养的 BEC 上调 OPN 和 TGF-β 的表达，并增强 HSC 中胶原-I 的合成。最后，重组 TGF-β（rTGFβ）和 rOPN 促进 BEC 增殖，OPN 和 TGF-β 的中和减少共培养的 HSC 中胶原-I 的表达。
OPN 作为一种关键的基质细胞蛋白，通过 TGF-β 驱动 DR 并促进瘢痕形成和肝纤维化。
