Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans
Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans
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DOI：
10.1172/jci35875
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发表时间：
2008-10-01
影响因子：
15.9
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Omenetti, Alessia;Porrello, Alessandro;Diehl, Anna Mae
上皮间质转化（EMT）在胚胎发生过程中的组织构建中发挥着重要作用，有证据表明这一过程也可能有助于在损伤后重塑一些成人组织。刺猬 (Hh) 信号通路的激活可调节发育过程中的 EMT。该途径也是由慢性胆道损伤诱导的，在这种情况下，EMT 被认为发挥了作用。我们评估了 Hh 信号传导促进成人胆管细胞（胆管细胞）EMT 的假设。在慢性胆道损伤患者的肝切片和从接受胆管结扎 (BDL)（胆道纤维化实验模型）的大鼠中分离的原代胆管细胞中，EMT 定位于具有 Hh 途径活性的胆管细胞。 BDL 大鼠胆管阻塞的缓解可降低 Hh 通路活性、EMT 和胆道纤维化。在小鼠胆管细胞中，与肌纤维母细胞肝星状细胞（可溶性 Hh 配体的来源）共培养可促进 EMT 和细胞迁移。在共培养物中添加 Hh 中和抗体可阻断这些效应。最后，我们发现修补缺陷小鼠对 BDL 的 EMT 反应增强，这些小鼠表现出 Hh 通路的过度激活。总之，这些数据表明 Hh 信号传导的激活促进 EMT 并有助于慢性胆汁淤积期间胆道纤维化的演变。
Epithelial-mesenchymal transitions (EMTs) play an important role in tissue construction during embryogenesis, and evidence suggests that this process may also help to remodel some adult tissues after injury. Activation of the hedgehog (Hh) signaling pathway regulates EMT during development. This pathway is also induced by chronic biliary injury, a condition in which EMT has been suggested to have a role. We evaluated the hypothesis that Hh signaling promotes EMT in adult bile ductular cells (cholangiocytes). In liver sections from patients with chronic biliary injury and in primary cholangiocytes isolated from rats that had undergone bile duct ligation (BDL), an experimental model of biliary fibrosis, EMT was localized to cholangiocytes with Hh pathway activity. Relief of ductal obstruction in BDL rats reduced Hh pathway activity, EMT, and biliary fibrosis. In mouse cholangiocytes, coculture with myofibroblastic hepatic stellate cells, a source of soluble Hh ligands, promoted EMT and cell migration. Addition of Hh-neutralizing antibodies to cocultures blocked these effects. Finally, we found that EMT responses to BDL were enhanced in patched-deficient mice, which display excessive activation of the Hh pathway. Together, these data suggest that activation of Hh signaling promotes EMT and contributes to the evolution of biliary fibrosis during chronic cholestasis.