Mitochondrial Function Controls Proliferation and Early Differentiation Potential of Embryonic Stem Cells§

Authors

  • Sudip Mandal,

    1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA
    2. Biology Division, Indian Institute of Science Education and Research, Mohali, Chandigarh, India
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  • Anne G. Lindgren,

    1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA
    2. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California, USA
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  • Anand S. Srivastava,

    1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA
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  • Amander T. Clark,

    Corresponding author
    1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA
    2. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California, USA
    3. Molecular Biology Institute, University of California, Los Angeles, California, USA
    • Department of Molecular, Cell and Developmental Biology, 620 Charles E Young Drive South, Los Angeles, California 90019, USA
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    • Telephone: (310) 794-4201

  • Utpal Banerjee

    Corresponding author
    1. Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, California, USA
    2. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California, USA
    3. Molecular Biology Institute, University of California, Los Angeles, California, USA
    4. Department of Biological Chemistry, University of California, Los Angeles, California, USA
    • Department of Molecular, Cell and Developmental Biology, 620 Charles E Young Drive South, Los Angeles, California 90019, USA
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    • Telephone: (310) 206-5439; Fax: (310) 206-9062


  • Disclosure of potential conflicts of interest is found at the end of this article.

  • Author contributions: S.M.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; A.G.L.: collection and/or assembly of data, data analysis and interpretation; A.S.S.: collection and/or assembly of data, manuscript writing; A.T.C.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, research supervision; U.B.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript, financial support, administrative support, research supervision. A.T.C. and U.B. are the cocommunicating authors of this article.

  • §

    First published online in STEM CELLSEXPRESS December 29, 2010.

Abstract

Pluripotent stem cells hold significant promise in regenerative medicine due to their unlimited capacity for self-renewal and potential to differentiate into any cell type of the body. In this study, we demonstrate that proper mitochondrial function is essential for proliferation of undifferentiated ESCs. Attenuating mitochondrial function under self-renewing conditions makes these cells more glycolytic-dependent, and it is associated with an increase in the mRNA reserves of Nanog, Oct4, and Sox2. In contrast, attenuating mitochondrial function during the first 7 days of differentiation results in normal repression of Oct4, Nanog, and Sox2. However, differentiation potential is compromised as revealed by abnormal transcription of multiple Hox genes. Furthermore, under differentiating conditions in which mitochondrial function is attenuated, tumorigenic cells continue to persist. Our results, therefore establish the importance of normal mitochondrial function in ESC proliferation, regulating differentiation, and preventing the emergence of tumorigenic cells during the process of differentiation. STEM CELLS 2011;486–495

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