title: Improvement of carbon tetrachloride-induced acute hepatic failure by transplantation of induced pluripotent stem cells without reprogramming factor c-Myc.
abstract: 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 (CCl(4))-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 CCl(4)-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 CCl(4)-treated mice. CCl(4)-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.
authors.affiliation: Department of Optics and Photonics, National Central University, Chung-Li, Taiwan.
authors.forename: Hua-Ming
authors.initials: HM
authors.lastname: Chang
authors.affiliation: Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liao
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.|Division of Urology, Department of Surgery, Taipei Veterans General Hospital and Su-Ao/Yuan-Shan Branch, Yilan County, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chiang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ying-Hsiu
authors.initials: YH
authors.lastname: Lai
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hen-Li
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Division of Urology, Department of Surgery, Taipei Veterans General Hospital and Su-Ao/Yuan-Shan Branch, Yilan County, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shaw-Yeu
authors.initials: SY
authors.lastname: Jeng
authors.affiliation: Division of Urology, Department of Surgery, Taipei Veterans General Hospital and Su-Ao/Yuan-Shan Branch, Yilan County, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jung-Hung
authors.initials: JH
authors.lastname: Hsieh
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Shin Kong Wu Ho-Su Memorial Hospital and Fu-Jen Catholic University, Taipei, Taiwan.
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Peng
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsin-Yang
authors.initials: HY
authors.lastname: Li
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Department of Optics and Photonics, National Central University, Chung-Li, Taiwan.
authors.forename: Szu-Yu
authors.initials: SY
authors.lastname: Chen
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Liang-Kung
authors.initials: LK
authors.lastname: Chen
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Teh-Ia
authors.initials: TI
authors.lastname: Huo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002454:Cell Differentiation; D002470:Cell Survival; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D056486:Chemical and Drug Induced Liver Injury / Q000628:therapy*; D004195:Disease Models, Animal; D006501:Hepatic Encephalopathy / Q000628:therapy*; D022781:Hepatocytes / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000637:transplantation*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C489428:Myc protein, mouse; D050814:Octamer Transcription Factor-3; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D002251:Carbon Tetrachloride