Peribiliary gland niche participates in biliary tree regeneration in mouse and in human primary sclerosing cholangitis.

Carpino G , Nevi L , Overi D , Cardinale V , Lu WY , Di Matteo S , Safarikia S , Berloco PB , Venere R , Onori P , Franchitto A , Forbes SJ , Alvaro D , Gaudio E
Hepatology (Baltimore, Md.)
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. Bile duct injury was induced by the administration of 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 14 days to Krt19 TdTomato mice. Human Biliary Tree Stem Cells (BTSC) within PBGs were isolated from extrahepatic biliary tree obtained from liver donors. Hepatic duct samples (N=10) were obtained from patients affected by Primary Sclerosing Cholangitis (PSC). Samples were analysed by histology, immunohistochemistry, western blotting, and PCR. 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 signalling pathway triggers human BTSC proliferation in vitro and influences PBG hyperplasia in vivo in the DDC-mediated mouse biliary injury model. The Notch signalling 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 signalling pathways. CONCLUSION: 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 patho-physiology and treatment of cholangiopaties. This article is protected by copyright. All rights reserved.

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