{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:13:12Z","timestamp":1791958392199,"version":"4.3.4"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20bm0404042h0002"],"award-info":[{"award-number":["20bm0404042h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A\u201083\u201001, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Primary hepatocytes were isolated from aged and young donor rats, respectively. Hepatic histological changes were evaluated. Differences in gene expression in hepatocytes were identified. The in vitro reprogramming plasticity of hepatocytes as evidenced by CLiP conversion and the hepatocyte and cholangiocyte maturation capacity of reprogrammed CLIPs were analyzed. The effect of hepatocyte growth factor (HGF) on cell propagation was also investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The histological findings revealed ongoing liver damage with inflammation, fibrosis, senescence, and ductular reaction in aged livers. Microarray analysis showed altered gene expression profiles in hepatocytes from aged donors, especially with regard to metabolic pathways. Aged hepatocytes could be converted into CLiPs (Aged\u2010CLiPs) expressing progenitor cell markers, but with a relatively low proliferative rate compared with young hepatocytes. Aged\u2010CLiPs possessed both hepatocyte and cholangiocyte maturation capacity. HGF facilitated CLiP conversion in aged hepatocytes, which was partly related to the activation of Erk1 and Akt1 signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Aged rat hepatocytes have retained reprogramming plasticity as evidenced by CLiP conversion in culture. HGF promoted proliferation and CLiP conversion in aged hepatocytes. Hepatocytes from aged donors may be used as an alternative cell source to mitigate donor shortage.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hepr.13609","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:45:34Z","timestamp":1609375534000},"page":"323-335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Chemical conversion of aged hepatocytes into bipotent liver progenitor cells"],"prefix":"10.1111","volume":"51","author":[{"given":"Yu","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"},{"name":"Department of Surgery School of Medicine Guangzhou First People's Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Miyamoto","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"},{"name":"Department of Surgery School of Medicine Guangzhou First People's Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"},{"name":"Department of Chemical Engineering Faculty of Engineering Graduate School Kyushu University  Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanobu","family":"Hara","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiko","family":"Soyama","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaaki","family":"Hidaka","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Kanetaka","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Li","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Surgery School of Medicine Guangzhou First People's Hospital South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susumu","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Department of Surgery Nagasaki University Graduate School of Biomedical Sciences  Nagasaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/ggi.12450"},{"key":"e_1_2_8_3_1","first-page":"1","article-title":"Regenerative medicine for the hepatobiliary system: A review","author":"Huang Y","year":"2020","journal-title":"J Hepatobiliary Pancreat Sci"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.10.007"},{"key":"e_1_2_8_5_1","first-page":"1","article-title":"Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes","volume":"70","author":"Katsuda T","year":"2019","journal-title":"eLife"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.09.007"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3727\/096368915X688669"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.06.046"},{"key":"e_1_2_8_9_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/3975689","article-title":"Development of Bifunctional Three\u2010Dimensional Cysts from Chemically Induced Liver Progenitors","volume":"2019","author":"Huang Y","year":"2019","journal-title":"Stem Cells Int"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molp.2020.06.009"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-018-0794-4"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbiosc.2020.07.009"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29400"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145084"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2019.07.021"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101184"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26937"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20650"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.05.012"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/859415"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24713"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/53A.2.B111"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-8961-4_11"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.01.007"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.03.017"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1159\/000346166"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1270"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0102-67202012000100011"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2005.04.002"}],"container-title":["Hepatology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hepr.13609","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/hepr.13609","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hepr.13609","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T05:28:25Z","timestamp":1693286905000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hepr.13609"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1111\/hepr.13609"],"URL":"https:\/\/doi.org\/10.1111\/hepr.13609","archive":["Portico"],"relation":{},"ISSN":["1386-6346","1872-034X"],"issn-type":[{"value":"1386-6346","type":"print"},{"value":"1872-034X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,22]]},"assertion":[{"value":"2020-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}