{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:52:58Z","timestamp":1791237178603,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T00:00:00Z","timestamp":1570665600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>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, <jats:italic toggle=\"yes\">in vivo<\/jats:italic> and <jats:italic toggle=\"yes\">in vitro<\/jats:italic>, the signaling pathways involved.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Bile duct injury was induced by the administration of 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine (DDC) diet for 14 days to Krt19<jats:sup>Cre<\/jats:sup>TdTomato<jats:sup>LSL<\/jats:sup> mice. Human biliary tree stem\/progenitor cells (BTSC) within PBGs were isolated from EHBT obtained from liver donors. Hepatic duct samples (n\u00a0=\u00a010) 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<jats:sup>\u2010<\/jats:sup>\/SOX9<jats:sup>+<\/jats:sup>) is involved in the renewal of surface epithelium in injured EHBT. The Wnt signaling pathway triggers human BTSC proliferation <jats:italic toggle=\"yes\">in vitro<\/jats:italic> and influences PBG hyperplasia <jats:italic toggle=\"yes\">in vivo<\/jats:italic> in the DDC\u2010mediated mouse biliary injury model. The Notch signaling pathway activation induces BTSC differentiation <jats:italic toggle=\"yes\">in vitro<\/jats:italic> 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\u2010regulation of the Wnt and Notch signaling pathways.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.30871","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T20:43:14Z","timestamp":1563828194000},"page":"972-989","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":51,"title":["Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis"],"prefix":"10.1097","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8570-2519","authenticated-orcid":false,"given":"Guido","family":"Carpino","sequence":"first","affiliation":[{"name":"Department of Movement, Human and Health Sciences, Division of Health Sciences,University of Rome \u201cForo Italico,\u201d,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0924-2551","authenticated-orcid":false,"given":"Lorenzo","family":"Nevi","sequence":"additional","affiliation":[{"name":"Department of Precision and Translational Medicine,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3561-8903","authenticated-orcid":false,"given":"Diletta","family":"Overi","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Cardinale","sequence":"additional","affiliation":[{"name":"Department of Medico\u2010Surgical Sciences and Biotechnologies,Sapienza University of Rome,Latina,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Yu","family":"Lu","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Regenerative Medicine,University of Edinburgh,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Di Matteo","sequence":"additional","affiliation":[{"name":"Department of Precision and Translational Medicine,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Safarikia","sequence":"additional","affiliation":[{"name":"Department of Precision and Translational Medicine,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale Bartolomeo","family":"Berloco","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Organ Transplantation,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Venere","sequence":"additional","affiliation":[{"name":"Department of Precision and Translational Medicine,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Onori","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Franchitto","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart J.","family":"Forbes","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Regenerative Medicine,University of Edinburgh,United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Alvaro","sequence":"additional","affiliation":[{"name":"Department of Precision and Translational Medicine,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Gaudio","sequence":"additional","affiliation":[{"name":"Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences,Sapienza University of Rome,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"key":"hep30871-bib-0001-20250501","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nrgastro.2012.23","article-title":"The biliary tree\u2013a reservoir of multipotent stem cells","volume":"9","year":"2012","journal-title":"Nat Rev Gastroenterol 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