title: Enhanced differentiation of three-gene-reprogrammed induced pluripotent stem cells into adipocytes via adenoviral-mediated PGC-1α overexpression.
abstract: Induced pluripotent stem cells formed by the introduction of only three factors, Oct4/Sox2/Klf4 (3-gene iPSCs), may provide a safer option for stem cell-based therapy than iPSCs conventionally introduced with four-gene iPSCs. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) plays an important role during brown fat development. However, the potential roles of PGC-1α in regulating mitochondrial biogenesis and the differentiation of iPSCs are still unclear. Here, we investigated the effects of adenovirus-mediated PGC-1α overexpression in 3-gene iPSCs. PGC-1α overexpression resulted in increased mitochondrial mass, reactive oxygen species production, and oxygen consumption. Microarray-based bioinformatics showed that the gene expression pattern of PGC-1α-overexpressing 3-gene iPSCs resembled the expression pattern observed in adipocytes. Furthermore, PGC-1α overexpression enhanced adipogenic differentiation and the expression of several brown fat markers, including uncoupling protein-1, cytochrome C, and nuclear respiratory factor-1, whereas it inhibited the expression of the white fat marker uncoupling protein-2. Furthermore, PGC-1α overexpression significantly suppressed osteogenic differentiation. These data demonstrate that PGC-1α directs the differentiation of 3-gene iPSCs into adipocyte-like cells with features of brown fat cells. This may provide a therapeutic strategy for the treatment of mitochondrial disorders and obesity.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; E-Mails:  pinihuang@gmail.com  (P.-I.H.);  khchen3@vghtpe.gov.tw  (K.-H.C.);  chpeng1008@gmail.com  (C.-H.P.).
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Yueh-Ching
authors.initials: YC
authors.lastname: Chou
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.forename: Yueh
authors.initials: Y
authors.lastname: Chien
authors.forename: Kuan-Hsuan
authors.initials: KH
authors.lastname: Chen
authors.forename: Wen-Shin
authors.initials: WS
authors.lastname: Song
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Peng
authors.forename: Chin-Hong
authors.initials: CH
authors.lastname: Chang
authors.forename: Shin-Da
authors.initials: SD
authors.lastname: Lee
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Lu
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Kuo
authors.forename: Chuan-Chih
authors.initials: CC
authors.lastname: Hsu
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.forename: Ming-Chi
authors.initials: MC
authors.lastname: Yung
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
chemical_list: D007473:Ion Channels; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D024101:Mitochondrial Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D050814:Octamer Transcription Factor-3; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C494174:Pou5f1 protein, mouse; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; C000604390:Ucp2 protein, mouse; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D045304:Cytochromes c