{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:19:35Z","timestamp":1786976375258,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"30","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201808620130"],"award-info":[{"award-number":["201808620130"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201808310180"],"award-info":[{"award-number":["201808310180"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Healthcare Materials"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cholangiocyte organoids provide a powerful platform for applications ranging from in vitro modeling to tissue engineering for regenerative medicine. However, their expansion and differentiation are typically conducted in animal\u2010derived hydrogels, which impede the full maturation of organoids into functional cholangiocytes. In addition, these hydrogels are poorly defined and complex, limiting the clinical applicability of organoids. In this study, a novel medium composition combined with synthetic polyisocyanopeptide (PIC) hydrogels to enhance the maturation of intrahepatic cholangiocyte organoids (ICOs) into functional cholangiocytes is utilized. ICOs cultured in the presence of sodium butyrate and valproic acid, a histone deacetylase inhibitor, and a Notch signaling activator, respectively, in PIC hydrogel exhibit a more mature phenotype, as evidenced by increased expression of key cholangiocyte markers, crucial for biliary function. Notably, mature cholangiocyte organoids in PIC hydrogel display apical\u2010out polarity, in contrast to the traditional basal\u2010out polarization of ICOs cultured in Matrigel. Moreover, these mature cholangiocyte organoids effectively model the biliary pro\u2010fibrotic response induced by transforming growth factor beta. Taken together, an animal\u2010free, chemically defined culture system that promotes the ICOs into mature cholangiocytes with apical\u2010out polarity, facilitating regenerative medicine applications and in vitro studies that require access to the apical membrane, is developed.<\/jats:p>","DOI":"10.1002\/adhm.202401511","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T04:07:33Z","timestamp":1721794053000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chemically Defined Organoid Culture System for Cholangiocyte Differentiation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2793-2134","authenticated-orcid":false,"given":"Zhenguo","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Pharmacology Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University  Universiteitsweg 99 Utrecht 3584 CG The Netherlands"},{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Uppsalalaan 8 Utrecht 3584 CT The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shicheng","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Uppsalalaan 8 Utrecht 3584 CT The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0651-5334","authenticated-orcid":false,"given":"Luc J.W.","family":"van der Laan","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute University Medical Center Rotterdam  Doctor Molewaterplein 40 Rotterdam 3015 GD The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8109-7657","authenticated-orcid":false,"given":"Kerstin","family":"Schneeberger","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Uppsalalaan 8 Utrecht 3584 CT The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1560-1074","authenticated-orcid":false,"given":"Rosalinde","family":"Masereeuw","sequence":"additional","affiliation":[{"name":"Division of Pharmacology Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University  Universiteitsweg 99 Utrecht 3584 CG The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8114-0560","authenticated-orcid":false,"given":"Bart","family":"Spee","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Faculty of Veterinary Medicine Utrecht University  Uppsalalaan 8 Utrecht 3584 CT The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,23]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-024-03692-6"},{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2022.06.004"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2022.868857"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.050"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1088\/1758-5090\/aac8fd"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.04.011"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-020-0199-8"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202000893"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/bioengineering6030059"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202200880"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17161-0"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11839"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2018.01.042"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1100541"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.201602461"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602309"},{"key":"e_1_2_10_14_2","first-page":"178","volume":"1","author":"Cayo M. A.","year":"2009","journal-title":"Am. J. Transl. Res."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0705117104"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5680"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tec.2020.0283"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.029140"},{"key":"e_1_2_10_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.22220"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202006116"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/stcltm\/szad079"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26764-0"},{"key":"e_1_2_10_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3294"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.09.039"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.12-8-942"},{"key":"e_1_2_10_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2008.08.027"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1995.1059"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2015.05.005"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2009.6"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2022.121473"},{"key":"e_1_2_10_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17510"},{"key":"e_1_2_10_28_1","volume":"8","author":"Lewis P. L.","year":"2018","journal-title":"Stem Cells Int."},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msec.2021.112119"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2015.01.009"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10112806"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201901658"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110379"},{"key":"e_1_2_10_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.108"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-023-04836-2"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26762-2"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.588066"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2015.01.003"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1097\/HC9.0000000000000018"},{"key":"e_1_2_10_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32107"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.07.026"},{"key":"e_1_2_10_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(02)00429-4"},{"key":"e_1_2_10_39_3","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2017.05.007"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31037"}],"container-title":["Advanced Healthcare Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.202401511","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T11:55:21Z","timestamp":1759751721000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adhm.202401511"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,23]]},"references-count":51,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["10.1002\/adhm.202401511"],"URL":"https:\/\/doi.org\/10.1002\/adhm.202401511","archive":["Portico"],"relation":{},"ISSN":["2192-2640","2192-2659"],"issn-type":[{"value":"2192-2640","type":"print"},{"value":"2192-2659","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,23]]},"assertion":[{"value":"2024-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2401511"}}