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Int. J. Mol. Sci. 2011, 12(11), 7554-7568; doi:10.3390/ijms12117554

Article

Enhanced Differentiation of Three-Gene-Reprogrammed Induced Pluripotent Stem Cells into Adipocytes via Adenoviral-Mediated PGC-1α Overexpression

Pin-I Huang ^1,2,3 , Yueh-Ching Chou ^4,5,6 , Yuh-Lih Chang ^4,6 , Yueh Chien ^4,7 , Kuan-Hsuan Chen ^1,6 , Wen-Shin Song ^2,8 , Chi-Hsien Peng ^1,9 , Chin-Hong Chang ¹⁰ , Shin-Da Lee ¹¹ , Kai-Hsi Lu ^2,12 , Yi-Jen Chen ^2,7 , Chia-Hua Kuo ¹³ , Chuan-Chih Hsu ¹⁰ , Hsin-Chen Lee ^4,*  and Ming-Chi Yung ^2,14,*

¹ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan ² School of Medicine, National Yang-Ming University, Taipei 112, Taiwan ³ Cancer center, Taipei Veterans General Hospital, Taipei 112, Taiwan ⁴ Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan ⁵ College of Pharmacology, Taipei Medical University, Taipei 110, Taiwan ⁶ Department of Pharmacy, Taipei Veterans General Hospital, Taipei 112, Taiwan ⁷ Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan ⁸ Department of Surgery, Cheng-Hsin General Hospital, Taipei 112, Taiwan ⁹ Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan ¹⁰ Department of Surgery, Chi-Mei Medical Center, Tainan 710, Taiwan ¹¹ Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, Taichung 404, Taiwan ¹² Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei 112, Taiwan ¹³ Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei 111, Taiwan ¹⁴ Divison of Cardiovascular Surgery, Department of Surgery, Taiwan Adventist Hospital, Taipei 105, Taiwan

* Authors to whom correspondence should be addressed.

Received: 5 August 2011; in revised form: 25 October 2011 / Accepted: 4 November 2011 / Published: 7 November 2011

(This article belongs to the Section Molecular Pathology)

Download PDF Full-Text [3052 KB, Updated Version, uploaded 8 November 2011 16:39 CET]

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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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