title: Reprogramming induced pluripotent stem cells in the absence of c-Myc for differentiation into hepatocyte-like cells.
abstract: Induced pluripotent stem cells (iPSCs) with four reprogramming factors (Oct-4/Sox2/Klf-4/c-Myc) have been shown to differentiate into hepatic lineages. However, it was unclear whether obviation of the c-Myc oncogene in iPSCs affected hepatic differentiation or inhibited in vivo tumor formation. In this study, we demonstrated that iPSCs without c-Myc had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) with biological functions. As detected using planar-radionuclide imaging and Hoechst labeling assays, these iPSCs and iPSC-Heps tended to mobilize to the injured liver area in thioacetamide (TAA)-treated mice. Intravenous transplantation of both iPSCs and iPSC-Heps but not mouse embryonic fibroblasts (MEFs) reduced the hepatic necrotic area, improved liver functions, and rescued TAA-treated mice from lethal acute hepatic failure (AHF). In addition, microarray-based bioinformatics and quantitative RT-PCR showed high expression of antioxidant genes in iPSCs and iPSC-Heps compared to MEFs. In vivo and in vitro studies of NAC pretreatment confirmed that iPSCs and iPSC-Heps potentially suppressed ROS production and activated antioxidant enzymes in TAA-injured livers. Six months after transplantation in TAA-treated mice, tumor formation was not seen in non-c-Myc iPSC grafts. Therefore, reprogramming adult somatic cells without c-Myc may prevent oxidative stress-induced damage and provide a safer alternative for hepatic regeneration in AHF.
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Hsin-Yang
authors.initials: HY
authors.lastname: Li
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Szu-Fu
authors.initials: SF
authors.lastname: Chen
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chiang
authors.forename: Shaw-Yeu
authors.initials: SY
authors.lastname: Jeng
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Liang-Kung
authors.initials: LK
authors.lastname: Chen
authors.forename: Shuen-Iu
authors.initials: SI
authors.lastname: Hung
authors.forename: Teh-Ia
authors.initials: TI
authors.lastname: Huo
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000628:therapy; D019295:Computational Biology; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000637:transplantation; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051741:Kruppel-Like Transcription Factors; D008077:Lipoproteins, LDL; D050814:Octamer Transcription Factor-3; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D055748:SOXB1 Transcription Factors