{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:15:55Z","timestamp":1788066955265,"version":"build-2784847793"},"reference-count":73,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fund of Scientific Research Flanders","doi-asserted-by":"publisher","award":["1S83021N"],"award-info":[{"award-number":["1S83021N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fund of Scientific Research Flanders","doi-asserted-by":"publisher","award":["1280923N"],"award-info":[{"award-number":["1280923N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fund of Scientific Research Flanders","doi-asserted-by":"publisher","award":["G042719N"],"award-info":[{"award-number":["G042719N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fund of Scientific Research Flanders","doi-asserted-by":"publisher","award":["FWO-SBO-QPG-359638-\u2018iPSC-LIMIC\u2019"],"award-info":[{"award-number":["FWO-SBO-QPG-359638-\u2018iPSC-LIMIC\u2019"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1S83021N"],"award-info":[{"award-number":["1S83021N"]}],"id":[{"id":"https:\/\/ror.org\/03qtxy027","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1280923N"],"award-info":[{"award-number":["1280923N"]}],"id":[{"id":"https:\/\/ror.org\/03qtxy027","id-type":"ROR","asserted-by":"publisher"}]},{"award":["G042719N"],"award-info":[{"award-number":["G042719N"]}],"id":[{"id":"https:\/\/ror.org\/03qtxy027","id-type":"ROR","asserted-by":"publisher"}]},{"award":["FWO-SBO-QPG-359638-\u2018iPSC-LIMIC\u2019"],"award-info":[{"award-number":["FWO-SBO-QPG-359638-\u2018iPSC-LIMIC\u2019"]}],"id":[{"id":"https:\/\/ror.org\/03qtxy027","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011878","name":"Vlaamse regering","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100011878","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04qxsrb28","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hepatic stellate cells (HSCs) are central drivers of liver fibrosis, yet their heterogeneity is often overlooked in human liver organoid models. Here, we investigated how HSC-intrinsic variability influences fibrotic phenotypes in multicellular liver organoids using induced pluripotent stem cell-derived HSCs (iHSCs) and primary HSCs (pHSCs). iHSCs derived from two different iPSC lines exhibited distinct differentiation phenotypes towards iHSCs. Consistently, co-culture of the hepatocyte-like cell line HepaRG with these two iHSC populations generated organoids with distinct fibrotic and hepatic features. BJ1-iHSC\/HepaRG organoids contained an approximately 2.9-fold higher proportion of CYP3A4-positive cells, whereas Sigma-iHSC\/HepaRG organoids showed around a 4-fold higher percentage of Sirius red-positive area. Single-cell RNA analysis further showed that the two iHSC populations differed in cell cycle distribution, HSC-related signatures, extracellular matrix-associated pathways, and matrisome enrichment. Similarly, human pHSCs cultured as organoids with HepaRG showed marked donor-dependent differences at baseline and after single acetaminophen, repeated thioacetamide or transforming growth factor beta treatment. Together, our findings suggest that HSC heterogeneity, whether iPSC-derived or donor-derived, is an important factor in fibrotic output and response variability in human liver organoid models and should be considered in model design, interpretation and comparison between studies.<\/jats:p>","DOI":"10.3390\/cells15171556","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:27:46Z","timestamp":1787920066000},"page":"1556","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Behaviour of iPSC-Derived and Donor-Derived Hepatic Stellate Cells in Organoid Cultures Is Highly Variable and Contributes to Fibrotic Outcome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1847-5464","authenticated-orcid":false,"given":"Yuwei","family":"Yang","sequence":"first","affiliation":[{"name":"Liver Cell Biology Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2530-5479","authenticated-orcid":false,"given":"Mina","family":"Kazemzadeh Dastjerd","sequence":"additional","affiliation":[{"name":"Liver Cell Biology Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayla","family":"Smout","sequence":"additional","affiliation":[{"name":"Liver Cell Biology Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Merens","sequence":"additional","affiliation":[{"name":"Liver Cell Biology Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6890-1401","authenticated-orcid":false,"given":"Burak","family":"Toprakhisar","sequence":"additional","affiliation":[{"name":"Liver Cell Biology Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussel, Belgium"},{"name":"Stem Cell Institute Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine M.","family":"Verfaillie","sequence":"additional","affiliation":[{"name":"Stem Cell Institute Leuven, Katholieke Universiteit Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0341-7648","authenticated-orcid":false,"given":"Christophe","family":"Chesn\u00e9","sequence":"additional","affiliation":[{"name":"Biopredic International SARL, Parc de la Bretech, 35760 Saint Gr\u00e9goire, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0990-7034","authenticated-orcid":false,"given":"Leo A. van","family":"Grunsven","sequence":"additional","affiliation":[{"name":"Liver Cell Biology Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussel, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41575-025-01068-6","article-title":"Hepatic stellate cells: Balancing homeostasis, hepatoprotection and fibrogenesis in health and disease","volume":"22","author":"Schwabe","year":"2025","journal-title":"Nat. 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