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

Guido Carpino, Lorenzo Nevi, Diletta Overi, Vincenzo Cardinale, Wei-Yu Lu, Sabina Di Matteo, Samira Safarikia, Pasquale Bartolomeo Berloco, Rosanna Venere, Paolo Onori , Antonio Franchitto, Stuart J Forbes, Domenico Alvaro, Eugenio Gaudio

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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 Krt19Cre TdTomatoLSL 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.
Original languageEnglish
Number of pages18
Issue number0
Early online date22 Jul 2019
Publication statusPublished - 2019


Dive into the research topics of 'Peribiliary gland niche participates in biliary tree regeneration in mouse and in human primary sclerosing cholangitis'. Together they form a unique fingerprint.

Cite this