{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:33:16Z","timestamp":1791516796208,"version":"4.3.4"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory disease of the biliary tract characterized by cellular senescence and periportal fibrogenesis. Specific disease features that are cell intrinsic and either genetically or epigenetically mediated remain unclear due in part to a lack of appropriate, patient\u2010specific, <jats:italic toggle=\"yes\">in vitro<\/jats:italic> models. Recently, our group developed systems to create induced pluripotent stem cell (iPSC)\u2010derived cholangiocytes (iDCs) and biliary epithelial organoids (cholangioids). We use these models to investigate whether PSC cholangiocytes are intrinsically predisposed to cellular senescence. Skin fibroblasts from healthy controls and subjects with PSC were reprogrammed to pluripotency, differentiated to cholangiocytes, and subsequently grown in three\u2010dimensional matrigel\u2010based culture to induce formation of cholangioids. RNA sequencing (RNA\u2010seq) on iDCs showed significant differences in gene expression patterns, including enrichment of pathways associated with cell cycle, senescence, and hepatic fibrosis, that correlate with PSC. These pathways also overlapped with RNA\u2010seq analysis on isolated cholangiocytes from subjects with PSC. Exome sequencing on the subjects with PSC revealed genetic variants of unknown significance in the genes identified in these pathways. Three\u2010dimensional culture revealed smaller size, lack of a central lumen, and increased cellular senescence in PSC\u2010derived cholangioids. Congruent with this, PSC\u2010derived iDCs showed increased secretion of the extracellular matrix molecule fibronectin as well as the inflammatory cytokines interleukin\u20106, and chemokine (C\u2010C motif) ligand 2. Conditioned media (CM) from PSC\u2010derived iDCs more potently activated hepatic stellate cells compared to control CM. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> We demonstrated efficient generation of iDCs and cholangioids from patients with PSC that show disease\u2010specific features. PSC cholangiocytes are intrinsically predisposed to cellular senescence. These features are unmasked following biliary differentiation of pluripotent stem cells and have functional consequences in epithelial organoids.<\/jats:p>","DOI":"10.1002\/hep4.1809","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T06:01:01Z","timestamp":1629957661000},"page":"345-360","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation"],"prefix":"10.1097","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6795-0121","authenticated-orcid":false,"given":"Nidhi","family":"Jalan\u2010Sakrikar","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Gastroenterology Research Unit,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago M.","family":"De Assuncao","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Gastroenterology Research Unit,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Navarro\u2010Corcuera","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Gastroenterology Research Unit,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feda H.","family":"Hamdan","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Gastroenterology Research Unit,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Loarca","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Basic Research in Digestive Diseases,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey A.","family":"Kirkeby","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary T.","family":"Resch","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"O\u2019Hara","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Basic Research in Digestive Diseases,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Cell Signaling in Gastroenterology,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Juran","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Basic Research in Digestive Diseases,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0437-681X","authenticated-orcid":false,"given":"Konstantinos N.","family":"Lazaridis","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Basic Research in Digestive Diseases,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Cell Signaling in Gastroenterology,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles B.","family":"Rosen","sequence":"additional","affiliation":[{"name":"William J. von Liebig Center for Transplantation and Clinical Regeneration,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie K.","family":"Heimbach","sequence":"additional","affiliation":[{"name":"William J. von Liebig Center for Transplantation and Clinical Regeneration,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0641-2930","authenticated-orcid":false,"given":"Timucin","family":"Taner","sequence":"additional","affiliation":[{"name":"William J. von Liebig Center for Transplantation and Clinical Regeneration,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7620-573X","authenticated-orcid":false,"given":"Vijay H.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Gastroenterology Research Unit,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Cell Signaling in Gastroenterology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"William J. von Liebig Center for Transplantation and Clinical Regeneration,Mayo Clinic and Foundation,Rochester,MN,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas F.","family":"LaRusso","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic and Foundation,Rochester,MN,USA"},{"name":"Center for Basic Research in Digestive Diseases,Mayo Clinic and 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