{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:41:42Z","timestamp":1781761302085,"version":"3.54.5"},"reference-count":29,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,12,26]],"date-time":"2019-12-26T00:00:00Z","timestamp":1577318400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["\u2018\u2018Center for Clinical Application Research on Specific Disease\/Organ,\u2019\u2019 Research Center Network for Realization of Regenerative Medicine"],"award-info":[{"award-number":["\u2018\u2018Center for Clinical Application Research on Specific Disease\/Organ,\u2019\u2019 Research Center Network for Realization of Regenerative Medicine"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this study, we reveal that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage. The liver organoids significantly reconstituted the hepatocytes; hence, the liver was significantly enlarged in this group, compared to the monolayer cell transplantation group in the retrorsine\/partial hepatectomy (RS\/PH) model. In the liver organoid transplantation group, the bile ducts were located in the donor area and connected to the recipient bile ducts. Thus, the rate of bile reconstruction in the liver was significantly higher compared to that in the monolayer group. By transplanting liver organoids, we saw a level of 70% replacement of the damaged liver. Consequently, in the transplantation group, diminished ductular reaction and a decrease of placental glutathione S-transferase (GST-p) precancerous lesions were observed. After trans-portal injection, the human induced pluripotent stem cell (hiPSC)-derived liver organoids revealed no translocation outside the liver; in contrast, the monolayer cells had spread to the lungs. The hiPSC-derived liver organoids were attached to the liver in the immunodeficient RS\/PH rats. This study clearly demonstrates that liver organoid transplantation through the portal vein is a safe and effective method for the treatment of chronic liver damage in rats.<\/jats:p>","DOI":"10.3390\/ijms21010178","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T05:37:08Z","timestamp":1577425028000},"page":"178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The Regenerative Effect of Portal Vein Injection of Liver Organoids by Retrorsine\/Partial Hepatectomy in Rats"],"prefix":"10.3390","volume":"21","author":[{"given":"Tomonori","family":"Tsuchida","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7367-301X","authenticated-orcid":false,"given":"Soichiro","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"},{"name":"Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichiro","family":"Matsuki","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Matsuo","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Mikami","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuharu","family":"Ueno","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"},{"name":"Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Tadokoro","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9002-3190","authenticated-orcid":false,"given":"Yun-Wen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"},{"name":"Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan"},{"name":"Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan"},{"name":"Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1002\/hep.21876","article-title":"Bile duct destruction by 4,4\u2019-diaminodiphenylmethane does not block the small hepatocyte-like progenitor cell response in retrorsine-exposed rats","volume":"46","author":"Best","year":"2007","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1542\/peds.111.6.1262","article-title":"Isolated hepatocyte transplantation in an infant with a severe urea cycle disorder","volume":"111","author":"Horsen","year":"2003","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1097\/TP.0b013e31823b72d6","article-title":"Current status of hepatocyte transplantation","volume":"93","author":"Hughes","year":"2012","journal-title":"Transplantation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/lt.23800","article-title":"Hepatocyte transplantation using a living donor reduced graft in a baby with ornithine transcarbamylase deficiency: A novel source of hepatocytes","volume":"20","author":"Enosawa","year":"2014","journal-title":"Liver Transpl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1016\/S0002-9440(10)65074-2","article-title":"Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation into adult rat liver","volume":"156","author":"Dabeva","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1053\/j.gastro.2005.10.049","article-title":"Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem\/progenitor cells","volume":"130","author":"Oertel","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1053\/j.gastro.2010.12.003","article-title":"Activin A, p15INK4b signaling, and cell competition promote stem\/progenitor cell repopulation of livers in aging rats","volume":"140","author":"Menthena","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature12271","article-title":"Vascularized and functional human liver from an iPSC-derived organ bud transplant","volume":"499","author":"Takebe","year":"2013","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/nprot.2014.020","article-title":"Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant","volume":"9","author":"Takebe","year":"2014","journal-title":"Nat. Protoc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.stem.2015.03.004","article-title":"Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation","volume":"16","author":"Takebe","year":"2015","journal-title":"Cell Stem. Cell."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1111\/j.1432-2277.2005.00127.x","article-title":"Portal vein thrombosis after intraportal hepatocytes transplantation in a liver transplant recipient","volume":"18","author":"Baccarani","year":"2005","journal-title":"Transpl. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.5966\/sctm.2015-0260","article-title":"Concise review: Updated advances and current challenges in cell therapy for inborn liver metabolic defects","volume":"5","author":"Najimi","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Stephenne, X., Nicastro, E., Eeckhoudt, S., Hermans, C., Nyabi, O., Lombard, C., Najimi, M., and Sokal, E. (2012). Bivalirudin in combination with heparin to control mesenchymal cell procoagulant activity. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042819"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.biomaterials.2014.11.019","article-title":"The effects of organoid formation of adipose-derived stem cells in a microgravity bioreactor on stemness properties and therapeutic potential","volume":"41","author":"Zhang","year":"2015","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1016\/j.biomaterials.2013.12.012","article-title":"An injectable organoid system with genetic modification for cell transplantation therapy","volume":"35","author":"Uchida","year":"2014","journal-title":"Biomaterials"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gabriel, E., Schievenbusch, S., Kolossov, E., Hengstler, J.G., Rotshteyn, T., Bohlen, H., Hengstler, J.G., Hescheler, J., and Drobinskaya, I. (2012). Differentiation and selection of hepatocyte precursors in suspension organoid culture of transgenic murine embryonic stem cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044912"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.surg.2018.04.012","article-title":"Hepatocyte organoids as an alternative to single cells for transplantation after ex vivo gene therapy in mice and pig models","volume":"164","author":"Nicolas","year":"2018","journal-title":"Surgery"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0168-8278(03)00231-9","article-title":"Hepatic sinusoidal-obstruction syndrome: Toxicity of pyrrolizidine alkaloids","volume":"39","author":"Chojkier","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0002-9440(10)65574-5","article-title":"Long term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine","volume":"153","author":"Laconi","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1365-2036.2006.02742.x","article-title":"Review article: Updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome","volume":"23","author":"Helmy","year":"2006","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1021\/acs.chemrestox.6b00260","article-title":"Comparative Study of Hepatotoxicity of Pyrrolizidine Alkaloids Retrorsine and Monocrotaline","volume":"30","author":"Yang","year":"2017","journal-title":"Chem. Res. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1053\/j.gastro.2013.11.034","article-title":"Links Between Hepatic Fibrosis, Ductular Reaction, and Progenitor Cell Expansion","volume":"146","author":"Williams","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1002\/hep.23488","article-title":"Progenitor-derived hepatocellular carcinoma model in the rat","volume":"51","author":"Andersen","year":"2010","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"R\u00f3kusz, A., Veres, D., Sz\u00fccs, A., Bugyik, E., M\u00f3zes, M., Paku, S., Nagy, P., and Dezso, K. (2017). Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176518"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1097\/00007890-200203270-00010","article-title":"Intraportal hepatocyte transplantation in the pig: Hemodynamic and histopathological study","volume":"73","author":"Muraca","year":"2002","journal-title":"Transplantation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3727\/215517912X639469","article-title":"Consideration of a safe protocol for hepatocyte transplantation using infantile pigs","volume":"3","author":"Enosawa","year":"2012","journal-title":"Cell Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/lt.500060113","article-title":"Hepatocyte transplantation in acute liver failure","volume":"6","author":"Bilir","year":"2000","journal-title":"Liver Transpl."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/hep.510230313","article-title":"Studies of liver repopulation using dipeptidyl peptidase IV deficient rats","volume":"23","author":"Rajvanshi","year":"1996","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1016\/j.celrep.2017.11.005","article-title":"Massive and Reproducible Production of Liver organoids Entirely from Human Pluripotent Stem Cells","volume":"21","author":"Takebe","year":"2017","journal-title":"Cell Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:45:48Z","timestamp":1760190348000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/1\/178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,26]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["ijms21010178"],"URL":"https:\/\/doi.org\/10.3390\/ijms21010178","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,26]]}}}