{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T06:02:31Z","timestamp":1778392951196,"version":"3.51.4"},"reference-count":70,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,15]],"date-time":"2019-11-15T00:00:00Z","timestamp":1573776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Domenico Alvaro","award":["000324_17_H2_ALVARO_H2020 - ALVARO - PROGETTI H2020 2017"],"award-info":[{"award-number":["000324_17_H2_ALVARO_H2020 - ALVARO - PROGETTI H2020 2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Human biliary tree stem\/progenitor cells (hBTSCs), reside in peribiliary glands, are mainly stimulated by primary sclerosing cholangitis (PSC) and cholangiocarcinoma. In these pathologies, hBTSCs displayed epithelial-to-mesenchymal transition (EMT), senescence characteristics, and impaired differentiation. Here, we investigated the effects of cholest-4,6-dien-3-one, an oxysterol involved in cholangiopathies, on hBTSCs biology. hBTSCs were isolated from donor organs, cultured in self-renewal control conditions, differentiated in mature cholangiocytes by specifically tailored medium, or exposed for 10 days to concentration of cholest-4,6-dien-3-one (0.14 mM). Viability, proliferation, senescence, EMT genes expression, telomerase activity, interleukin 6 (IL6) secretion, differentiation capacity, and HDAC6 gene expression were analyzed. Although the effect of cholest-4,6-dien-3-one was not detected on hBTSCs viability, we found a significant increase in cell proliferation, senescence, and IL6 secretion. Interestingly, cholest-4.6-dien-3-one impaired differentiation in mature cholangiocytes and, simultaneously, induced the EMT markers, significantly reduced the telomerase activity, and induced HDAC6 gene expression. Moreover, cholest-4,6-dien-3-one enhanced bone morphogenic protein 4 (Bmp-4) and sonic hedgehog (Shh) pathways in hBTSCs. The same pathways activated by human recombinant proteins induced the expression of EMT markers in hBTSCs. In conclusion, we demonstrated that chronic exposition of cholest-4,6-dien-3-one induced cell proliferation, EMT markers, and senescence in hBTSC, and also impaired the differentiation in mature cholangiocytes.<\/jats:p>","DOI":"10.3390\/cells8111443","type":"journal-article","created":{"date-parts":[[2019,11,15]],"date-time":"2019-11-15T11:25:56Z","timestamp":1573817156000},"page":"1443","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Cholest-4,6-Dien-3-One Promote Epithelial-To-Mesenchymal Transition (EMT) in Biliary Tree Stem\/Progenitor Cell Cultures In Vitro"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0924-2551","authenticated-orcid":false,"given":"Lorenzo","family":"Nevi","sequence":"first","affiliation":[{"name":"Department of Translation and Precision Medicine, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniele","family":"Costantini","sequence":"additional","affiliation":[{"name":"Department of Translation and Precision Medicine, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samira","family":"Safarikia","sequence":"additional","affiliation":[{"name":"Department of Translation and Precision Medicine, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina","family":"Di Matteo","sequence":"additional","affiliation":[{"name":"Department of Translation and Precision Medicine, \u201cSapienza\u201d University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Melandro","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Organ Transplantation, Sapienza University of Rome, 0016 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale Bartolomeo","family":"Berloco","sequence":"additional","affiliation":[{"name":"Department of General Surgery and Organ Transplantation, Sapienza University of Rome, 0016 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Cardinale","sequence":"additional","affiliation":[{"name":"Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, \u201cSapienza\u201d University of Rome, 04100 Latina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1002\/hep.30210","article-title":"Neoplastic Transformation of the Peribiliary Stem Cell Niche in Cholangiocarcinoma Arisen in Primary Sclerosing Cholangitis","volume":"69","author":"Carpino","year":"2019","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1056\/NEJMra1506330","article-title":"Primary Sclerosing Cholangitis","volume":"375","author":"Lazaridis","year":"2016","journal-title":"N. 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