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.
Keywords: induced pluripotent stem cell; c-Myc; peroxisome proliferator-activated receptor gamma coactivator-1α; brown adipocyte
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Huang, P.-I.; Chou, Y.-C.; Chang, Y.-L.; Chien, Y.; Chen, K.-H.; Song, W.-S.; Peng, C.-H.; Chang, C.-H.; Lee, S.-D.; Lu, K.-H.; Chen, Y.-J.; Kuo, C.-H.; Hsu, C.-C.; Lee, H.-C.; Yung, M.-C. Enhanced Differentiation of Three-Gene-Reprogrammed Induced Pluripotent Stem Cells into Adipocytes via Adenoviral-Mediated PGC-1α Overexpression. Int. J. Mol. Sci. 2011, 12, 7554-7568.
Huang P-I, Chou Y-C, Chang Y-L, Chien Y, Chen K-H, Song W-S, Peng C-H, Chang C-H, Lee S-D, Lu K-H, Chen Y-J, Kuo C-H, Hsu C-C, Lee H-C, Yung M-C. Enhanced Differentiation of Three-Gene-Reprogrammed Induced Pluripotent Stem Cells into Adipocytes via Adenoviral-Mediated PGC-1α Overexpression. International Journal of Molecular Sciences. 2011; 12(11):7554-7568.
Huang, Pin-I; Chou, Yueh-Ching; Chang, Yuh-Lih; Chien, Yueh; Chen, Kuan-Hsuan; Song, Wen-Shin; Peng, Chi-Hsien; Chang, Chin-Hong; Lee, Shin-Da; Lu, Kai-Hsi; Chen, Yi-Jen; Kuo, Chia-Hua; Hsu, Chuan-Chih; Lee, Hsin-Chen; Yung, Ming-Chi. 2011. "Enhanced Differentiation of Three-Gene-Reprogrammed Induced Pluripotent Stem Cells into Adipocytes via Adenoviral-Mediated PGC-1α Overexpression." Int. J. Mol. Sci. 12, no. 11: 7554-7568.