{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:32:19Z","timestamp":1791232339695,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2012,3,16]],"date-time":"2012-03-16T00:00:00Z","timestamp":1331856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl4)-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl4-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl4-treated mice. CCl4-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases.<\/jats:p>","DOI":"10.3390\/ijms13033598","type":"journal-article","created":{"date-parts":[[2012,3,16]],"date-time":"2012-03-16T12:14:35Z","timestamp":1331900075000},"page":"3598-3617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Improvement of Carbon Tetrachloride-Induced Acute Hepatic Failure by Transplantation of Induced Pluripotent Stem Cells without Reprogramming Factor c-Myc"],"prefix":"10.3390","volume":"13","author":[{"given":"Hua-Ming","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Optics and Photonics, National Central University, Chung-Li 32001, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Wen","family":"Liao","sequence":"additional","affiliation":[{"name":"Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hung","family":"Chiang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Division of Urology, Department of Surgery, Taipei Veterans General Hospital, Su-Ao\/Yuan-Shan Branch, Yilan County 26444, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Hsiu","family":"Lai","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuh-Lih","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hen-Li","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaw-Yeu","family":"Jeng","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Taipei Veterans General Hospital, Su-Ao\/Yuan-Shan Branch, Yilan County 26444, Taiwan"},{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Hung","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Taipei Veterans General Hospital, Su-Ao\/Yuan-Shan Branch, Yilan County 26444, Taiwan"},{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Hsien","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan"},{"name":"School of Medicine, Fu-Jen Catholic University, Taipei 24352, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Yang","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh","family":"Chien","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szu-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Optics and Photonics, National Central University, Chung-Li 32001, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Kung","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teh-Ia","family":"Huo","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2012,3,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.3748\/wjg.15.3086","article-title":"An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure","volume":"15","author":"Tunon","year":"2009","journal-title":"World J. Gastroenterol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1111\/j.1582-4934.2007.00162.x","article-title":"Hepatic tissue engineering: From transplantation to customized cell-based liver directed therapies from the laboratory","volume":"12","author":"Fiegel","year":"2008","journal-title":"J. Cell. Mol. Med"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1002\/hep.21441","article-title":"Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver","volume":"44","author":"Heo","year":"2006","journal-title":"Hepatology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature05934","article-title":"Generation of germline-competent induced pluripotent stem cells","volume":"448","author":"Okita","year":"2007","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1126\/science.1151526","article-title":"Induced pluripotent stem cell lines derived from human somatic cells","volume":"318","author":"Yu","year":"2007","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/hep.23354","article-title":"Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells","volume":"51","author":"Noto","year":"2010","journal-title":"Hepatology"},{"key":"ref_8","first-page":"98","article-title":"Directed differentiation of murine-induced pluripotent stem cells to functional hepatocyte-like cells","volume":"54","author":"Roelandt","year":"2010","journal-title":"J. Hepatol"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1172\/JCI43122","article-title":"Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells","volume":"120","author":"Rashid","year":"2010","journal-title":"J. Clin. Invest"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1161\/STROKEAHA.109.563015","article-title":"The postischemic environment differentially impacts teratoma or tumor formation after transplantation of human embryonic stem cell-derived neural progenitors","volume":"41","author":"Seminatore","year":"2010","journal-title":"Stroke"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1089\/scd.2009.0452","article-title":"Functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue","volume":"19","author":"Chen","year":"2010","journal-title":"Stem Cells Dev"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5994","DOI":"10.1016\/j.biomaterials.2011.05.009","article-title":"Reprogramming induced pluripotent stem cells in the absence of c-myc for differentiation into hepatocyte-like cells","volume":"32","author":"Li","year":"2011","journal-title":"Biomaterials"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.3109\/00498258809042255","article-title":"Ethanol feeding stimulates trichloromethyl radical formation from carbon tetrachloride in liver","volume":"18","author":"Reinke","year":"1988","journal-title":"Xenobiotica"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1002\/stem.307","article-title":"Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells","volume":"28","author":"Armstrong","year":"2010","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s00535-008-2297-z","article-title":"Hepatic stem\/progenitor cells and stem-cell transplantation for the treatment of liver disease","volume":"44","author":"Kakinuma","year":"2009","journal-title":"J. Gastroenterol"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.bbmt.2008.11.021","article-title":"Successful hematopoietic stem cell transplantation from an hla-identical sibling in a patient with aplastic anemia after hla-haploidentical living-related liver transplantation for fulminant hepatitis","volume":"15","author":"Yoshimi","year":"2009","journal-title":"Biol. Blood Marrow Transplant"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2174\/157488809788167418","article-title":"Stem cell research and therapy for liver disease","volume":"4","author":"Kobayashi","year":"2009","journal-title":"Curr. Stem Cell Res. Ther"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nbt1374","article-title":"Generation of induced pluripotent stem cells without myc from mouse and human fibroblasts","volume":"26","author":"Nakagawa","year":"2008","journal-title":"Nat. Biotechnol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0378-4274(02)00333-8","article-title":"Role of metabolism by flavin-containing monooxygenase in thioacetamide-induced immunosuppression","volume":"136","author":"Lee","year":"2003","journal-title":"Toxicol. Lett"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1186\/1476-5926-2-S1-S6","article-title":"Thioredoxin prevents thioacetamide-induced acute hepatitis","volume":"3","author":"Okuyama","year":"2004","journal-title":"Comp. Hepatol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/S0168-8278(03)00504-X","article-title":"Melatonin inhibits nuclear factor kappa b activation and oxidative stress and protects against thioacetamide induced liver damage in rats","volume":"40","author":"Bruck","year":"2004","journal-title":"J. Hepatol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1046\/j.1439-0264.2002.00359.x","article-title":"Level of superoxide dismutase, glutathione peroxidase and uric acid in thioacetamide-induced cirrhotic rats","volume":"31","author":"Abul","year":"2002","journal-title":"Anat. Histol. Embryol"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1006\/taap.1999.8729","article-title":"Effect of thioacetamide on the hepatic expression of gamma-glutamylcysteine synthetase subunits in the rat","volume":"159","author":"Lu","year":"1999","journal-title":"Toxicol. Appl. Pharmacol"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S0168-8278(03)00050-3","article-title":"The effects of early and late administration of inhibitors of inducible nitric oxide synthase in a thioacetamide-induced model of acute hepatic failure in the rat","volume":"38","author":"Rahman","year":"2003","journal-title":"J. Hepatol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"866","DOI":"10.3748\/wjg.v13.i6.866","article-title":"Embryonic stem cells develop into hepatocytes after intrasplenic transplantation in ccl4-treated mice","volume":"13","author":"Moriya","year":"2007","journal-title":"World J. Gastroenterol"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1053\/j.gastro.2008.03.015","article-title":"Stem cell therapy for liver disease: Parameters governing the success of using bone marrow mesenchymal stem cells","volume":"134","author":"Kuo","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.biomaterials.2010.08.101","article-title":"Stem cell homing in musculoskeletal injury","volume":"32","author":"Fong","year":"2011","journal-title":"Biomaterials"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1111\/j.1582-4934.2009.00912.x","article-title":"Recruitment of endogenous bone marrow mesenchymal stem cells towards injured liver","volume":"14","author":"Chen","year":"2010","journal-title":"J. Cell. Mol. Med"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/S0022-3565(25)28988-1","article-title":"The route of absorption of intraperitoneally administered compounds","volume":"178","author":"Lukas","year":"1971","journal-title":"J. Pharmacol. Exp. Ther"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/qjmed\/hcp152","article-title":"Current concepts in the assessment and treatment of hepatic encephalopathy","volume":"103","author":"Cash","year":"2010","journal-title":"QJM"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1089\/scd.2009.0186","article-title":"Resveratrol promotes osteogenic differentiation and protects against dexamethasone damage in murine induced pluripotent stem cells","volume":"19","author":"Kao","year":"2010","journal-title":"Stem Cells Dev"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1038\/cr.2009.107","article-title":"Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells","volume":"19","author":"Song","year":"2009","journal-title":"Cell Res"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e2637","DOI":"10.1371\/journal.pone.0002637","article-title":"Oct-4 expression maintained cancer stem-like properties in lung cancer-derived cd133-positive cells","volume":"3","author":"Chen","year":"2008","journal-title":"PLoS One"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1161\/01.RES.0000099504.30207.F5","article-title":"Contrasting roles of nadph oxidase isoforms in pressure-overload versus angiotensin ii-induced cardiac hypertrophy","volume":"93","author":"Byrne","year":"2003","journal-title":"Circ. Res"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/1550-2783-2-2-38","article-title":"The antioxidant role of glutathione and n-acetyl-cysteine supplements and exercise-induced oxidative stress","volume":"2","author":"Kerksick","year":"2005","journal-title":"J. Int. Soc. Sports Nutr"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/hep.1840150104","article-title":"Intrasplenic hepatocellular transplantation corrects hepatic encephalopathy in portacaval-shunted rats","volume":"15","author":"Ribeiro","year":"1992","journal-title":"Hepatology"},{"key":"ref_37","first-page":"263","article-title":"Establishment of an animal model of hepatic encephalopathy","volume":"63","author":"Chu","year":"2000","journal-title":"Zhonghua Yi Xue Za Zhi (Taipei)"}],"updated-by":[{"DOI":"10.3390\/ijms27125403","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2012,3,16]],"date-time":"2012-03-16T00:00:00Z","timestamp":1331856000000}}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/13\/3\/3598\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T02:10:22Z","timestamp":1781748622000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/13\/3\/3598"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3,16]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2012,3]]}},"alternative-id":["ijms13033598"],"URL":"https:\/\/doi.org\/10.3390\/ijms13033598","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,3,16]]}}}