{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:02:38Z","timestamp":1789164158140,"version":"build-2803163510"},"reference-count":63,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA222571"],"award-info":[{"award-number":["R01CA222571"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AI154722"],"award-info":[{"award-number":["R01AI154722"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK119937"],"award-info":[{"award-number":["R01DK119937"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AR070877"],"award-info":[{"award-number":["R01AR070877"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["HHSN261200800001E"],"award-info":[{"award-number":["HHSN261200800001E"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Hepatocyte organoids (HOs) generated in vitro are powerful tools for liver regeneration. However, previously reported HOs have mostly been fetal in nature with low expression levels of metabolic genes characteristic of adult liver functions, hampering their application in studies of metabolic regulation and therapeutic testing for liver disorders. Here, we report development of novel culture conditions that combine optimized levels of triiodothyronine (T3) with the removal of growth factors to enable successful generation of mature hepatocyte organoids (MHOs) of both mouse and human origin with metabolic functions characteristic of adult livers. We show that the MHOs can be used to study various metabolic functions including bile and urea production, zonal metabolic gene expression, and metabolic alterations in both alcoholic liver disease and non-alcoholic fatty liver disease, as well as hepatocyte proliferation, injury and cell fate changes. Notably, MHOs derived from human fetal hepatocytes also show improved hepatitis B virus infection. Therefore, these MHOs provide a powerful in vitro model for studies of human liver physiology and diseases. The human MHOs are potentially also a robust research tool for therapeutic development.<\/jats:p>","DOI":"10.1242\/jcs.261961","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T14:26:07Z","timestamp":1714746367000},"source":"Crossref","is-referenced-by-count":14,"title":["Generation and characterization of mature hepatocyte organoids for liver metabolic studies"],"prefix":"10.1242","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8922-9976","authenticated-orcid":false,"given":"Yuchen","family":"Liu","sequence":"first","affiliation":[{"name":"Harvard School of Dental Medicine 1 Department of Developmental Biology , , 188 Longwood Ave, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Harvard School of Dental Medicine 1 Department of Developmental Biology , , 188 Longwood Ave, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Ahodantin","sequence":"additional","affiliation":[{"name":"Institute of Human Virology 2 Division of Virology, Pathogenesis, and Cancer , , Departments of Pharmacology and Microbiology and Immunology , , Baltimore, MD 21201 , USA"},{"name":"University of Maryland School of Medicine 2 Division of Virology, Pathogenesis, and Cancer , , Departments of Pharmacology and Microbiology and Immunology , , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Jin","sequence":"additional","affiliation":[{"name":"Harvard School of Dental Medicine 1 Department of Developmental Biology , , 188 Longwood Ave, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Harvard School of Dental Medicine 1 Department of Developmental Biology , , 188 Longwood Ave, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonghe","family":"Sun","sequence":"additional","affiliation":[{"name":", Frederick National Laboratory for Cancer, Leidos Biomedical Research, Inc. 3 Cancer Research Technology Program , Frederick, MD 21702 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Wu","sequence":"additional","affiliation":[{"name":", Frederick National Laboratory for Cancer, Leidos Biomedical Research, Inc. 3 Cancer Research Technology Program , Frederick, MD 21702 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishan","family":"Su","sequence":"additional","affiliation":[{"name":"Institute of Human Virology 2 Division of Virology, Pathogenesis, and Cancer , , Departments of Pharmacology and Microbiology and Immunology , , Baltimore, MD 21201 , USA"},{"name":"University of Maryland School of Medicine 2 Division of Virology, Pathogenesis, and Cancer , , Departments of Pharmacology and Microbiology and Immunology , , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3933-887X","authenticated-orcid":false,"given":"Yingzi","family":"Yang","sequence":"additional","affiliation":[{"name":"Harvard School of Dental Medicine 1 Department of Developmental Biology , , 188 Longwood Ave, Boston, MA 02115 , USA"},{"name":"Harvard Stem Cell Institute 4 , Program in Gastrointestinal Malignancies , , 188 Longwood Ave, Boston, MA 02115 , USA"},{"name":"Dana-Farber\/Harvard Cancer Center 4 , Program in Gastrointestinal Malignancies , , 188 Longwood Ave, Boston, MA 02115 , USA"},{"name":"Dana-Farber\/Harvard Cancer Center 5 Program in Gastrointestinal Malignancies , , 188 Longwood Ave, Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2024,5,28]]},"reference":[{"key":"2024080908260500000_JCS261961C1","doi-asserted-by":"publisher","first-page":"2645","DOI":"10.1038\/s41388-018-0607-3","article-title":"Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation","volume":"38","author":"Ahodantin","year":"2019","journal-title":"Oncogene"},{"key":"2024080908260500000_JCS261961C2","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1016\/j.stem.2021.04.001","article-title":"Principles of signaling pathway modulation for enhancing human naive pluripotency induction","volume":"28","author":"Bayerl","year":"2021","journal-title":"Cell Stem Cell"},{"key":"2024080908260500000_JCS261961C3","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1007\/s00204-018-2371-0","article-title":"Acetaminophen cytotoxicity in HepG2 cells is associated with a decoupling of glycolysis from the TCA cycle, loss of NADPH production, and suppression of anabolism","volume":"93","author":"Behrends","year":"2019","journal-title":"Arch. 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