Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis
Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis
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DOI：
10.1002/hep.30871
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发表时间：
2019-10-10
期刊：
影响因子：
13.5
通讯作者：
Gaudio, Eugenio
中科院分区：
文献类型：
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作者：
Carpino, Guido;Nevi, Lorenzo;Gaudio, Eugenio
背景和目的肝外胆管树（EHBT）损伤后修复的机制尚不清楚。本研究的目的是评估，通过使用谱系追踪的方法，在EHBT损伤后的再生中的胆管周围腺（PBG）龛的贡献，并评估，在体内和体外，所涉及的信号通路。方法和结果通过给予Krt 19（Cre）TdTomato（LSL）小鼠3，5-二乙氧羰基-1，4-二氢可力丁（DDC）饲料14天诱导胆管损伤。从获自肝脏供体的EHBT中分离PBG内的人胆管树干/祖细胞（BTSC）。肝管样本（n = 10）从原发性硬化性胆管炎（PSC）患者获得。通过组织学、免疫组织化学、蛋白质印迹和聚合酶链反应分析样品。DDC给药导致EHBT中PBG增生和导管周围纤维化。PBG细胞群（细胞角蛋白19（-）/SOX 9（+））参与损伤的EHBT中表面上皮的更新。在DDC介导的小鼠胆道损伤模型中，Wnt信号通路在体外触发人BTSC增殖并在体内影响PBG增生。Notch信号通路激活诱导BTSC在体外向成熟胆管细胞分化，并与DDC模型中的PBG激活相关。在人PSC中，炎性细胞和基质细胞通过上调Wnt和Notch信号通路触发PBG活化。结论我们证实了PBG细胞参与了损伤胆管上皮的再生，并确定了驱动BTSC活化的信号通路。这些结果可能对胆管疾病的病理生理学和治疗具有相关意义。
Background and Aims Mechanisms underlying the repair of extrahepatic biliary tree (EHBT) after injury have been scarcely explored. The aims of this study were to evaluate, by using a lineage tracing approach, the contribution of peribiliary gland (PBG) niche in the regeneration of EHBT after damage and to evaluate, in vivo and in vitro, the signaling pathways involved. Approach and Results Bile duct injury was induced by the administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 14 days to Krt19(Cre)TdTomato(LSL) mice. Human biliary tree stem/progenitor cells (BTSC) within PBGs were isolated from EHBT obtained from liver donors. Hepatic duct samples (n = 10) were obtained from patients affected by primary sclerosing cholangitis (PSC). Samples were analyzed by histology, immunohistochemistry, western blotting, and polymerase chain reaction. DDC administration causes hyperplasia of PBGs and periductal fibrosis in EHBT. A PBG cell population (Cytokeratin19(-)/SOX9(+)) is involved in the renewal of surface epithelium in injured EHBT. The Wnt signaling pathway triggers human BTSC proliferation in vitro and influences PBG hyperplasia in vivo in the DDC-mediated mouse biliary injury model. The Notch signaling pathway activation induces BTSC differentiation in vitro toward mature cholangiocytes and is associated with PBG activation in the DDC model. In human PSC, inflammatory and stromal cells trigger PBG activation through the up-regulation of the Wnt and Notch signaling pathways. Conclusions We demonstrated the involvement of PBG cells in regenerating the injured biliary epithelium and identified the signaling pathways driving BTSC activation. These results could have relevant implications on the pathophysiology and treatment of cholangiopathies.