{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T15:35:07Z","timestamp":1775144107370,"version":"3.50.1"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFA0111300"],"award-info":[{"award-number":["2019YFA0111300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFA0903400"],"award-info":[{"award-number":["2018YFA0903400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research Grants Council of Hong Kong","award":["24204819"],"award-info":[{"award-number":["24204819"]}]},{"name":"Research Grants Council of Hong Kong","award":["N_CUHK432\/20"],"award-info":[{"award-number":["N_CUHK432\/20"]}]},{"name":"Research Grants Council of Hong Kong","award":["CUHK 14201317"],"award-info":[{"award-number":["CUHK 14201317"]}]},{"name":"Sichuan Science and Technology Program","award":["2022YFS0610"],"award-info":[{"award-number":["2022YFS0610"]}]},{"name":"Sichuan Science and Technology Program","award":["8601014"],"award-info":[{"award-number":["8601014"]}]},{"DOI":"10.13039\/501100004853","name":"Chinese University of Hong Kong","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004853","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cholangiocytes form a complex 3D network of bile ducts in the liver and contribute to liver function. The damage or destruction of cholangiocytes can lead to biliary diseases, and the shortage of cholangiocytes remains an obstacle for drug development targeting biliary diseases. Valproic acid (VPA) is a potent activator of Notch signaling pathway that is essential for cholangiocyte differentiation. Here, we report a VPA-based approach for cholangiocyte differentiation of human pluripotent stem cells. VPA activated Notch2 expression and upregulated HES-1, HEY-1, and Sox9 gene expression in hESC-derived hepatoblast. After 7 days treatment, VPA promoted successful differentiation of hepatoblast into cholangiocytes expressing cholangiocyte marker genes (AE2, AQP1, CFTR) and proteins (CK19 and CK7). In addition, the differentiated cholangiocytes formed bile duct-like structures after implantation into the spleen of NOD\/SCID mice. Our results suggested that VPA can promote hESC differentiation to cholangiocyte-like cells. The induced cholangiocytes may serve as a potential cell source for both in vitro modeling and regenerative therapy of cholangiopathies. The findings can also support further development of small-molecule based differentiation protocols for cholangiocyte production.<\/jats:p>","DOI":"10.1093\/stcltm\/szad079","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T21:05:16Z","timestamp":1700773516000},"page":"166-176","source":"Crossref","is-referenced-by-count":4,"title":["Effect of Valproic Acid on Promoting the Differentiation of Human Embryonic Stem Cells Into Cholangiocyte-Like Cells"],"prefix":"10.1093","volume":"13","author":[{"given":"Shuai","family":"Deng","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University , Luzhou , People\u2019s Republic of China"},{"name":"Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyan","family":"Kou","sequence":"additional","affiliation":[{"name":"Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanlun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Center for Neuromusculoskeletal Restorative Medicine , Hong Kong SAR , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuerao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-1251","authenticated-orcid":false,"given":"Hon Fai","family":"Chan","sequence":"additional","affiliation":[{"name":"Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR , People\u2019s Republic of China"},{"name":"Center for Neuromusculoskeletal Restorative Medicine , Hong Kong SAR , People\u2019s Republic of China"},{"name":"Hong Kong Branch of CAS Center for Excellence in Animal Evolution and Genetics , Hong Kong SAR , People\u2019s Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,11,23]]},"reference":[{"key":"2024021623444292600_CIT0001","first-page":"123","article-title":"Bile acid signaling and biliary functions","volume-title":"Acta Pharmaceut Sin B","author":"Jones","year":"2015"},{"key":"2024021623444292600_CIT0002","first-page":"269","article-title":"Cholangiocyte pathobiology","volume-title":"Nat Rev Gastroenterol Hepatol","author":"Banales","year":"2019"},{"key":"2024021623444292600_CIT0003","first-page":"653","article-title":"Functional anatomy of 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