Nicotinamide Overcomes Pluripotency Deficits and Reprogramming Barriers§

Authors

  • Myung Jin Son,

    1. Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
    2. Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea
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  • Mi-Young Son,

    1. Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
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  • Binna Seol,

    1. Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
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  • Min-Jeong Kim,

    1. Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
    2. Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea
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  • Chae Hwa Yoo,

    1. Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
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  • Myung-Kwan Han,

    1. Department of Microbiology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Republic of Korea
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  • Yee Sook Cho

    Corresponding author
    1. Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
    2. Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea
    • Regenerative Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Republic of Korea
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    • Telephone: 82-42-860-4479; Fax 82-42-860-4608


  • Author contributions: M.J.S., M.S.: Conception and design, Collection and/or assembly of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. B.S., M.K., C.H.Y.: Collection and/or assembly of data. M.H.: Conception and design. Y.S.C.: Conception and design, Financial support, Data analysis and interpretation, Manuscript writing, Final approval of manuscript. MJS and MS contributed equally to this article.

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

  • §

    first published online in STEM CELLS EXPRESS February 4, 2013.

Abstract

Crosstalk between intracellular signaling pathways has been extensively studied to understand the pluripotency of human pluripotent stem cells (hPSCs), including human embryonic stem cells and human induced pluripotent stem cells (hiPSCs); however, the contribution of NAD+-dependent pathways remains largely unknown. Here, we show that NAD+ depletion by FK866 (a potent inhibitor of NAD+ biosynthesis) was fatal in hPSCs, particularly when deriving pluripotent cells from somatic cells and maintaining pluripotency. NAD and its precursors (nicotinamide [NAM] and nicotinic acid) fully replenished the NAD+ depletion by FK866 in hPSCs. However, only NAM effectively enhanced the reprogramming efficiency and kinetics of hiPSC generation and was also significantly advantageous for the maintenance of undifferentiated hPSCs. Our molecular and functional studies reveal that NAM lowers the barriers to reprogramming by accelerating cell proliferation and protecting cells from apoptosis and senescence by alleviating oxidative stress, reactive oxygen species accumulation, and subsequent mitochondrial membrane potential collapse. We provide evidence that the positive effects of NAM (occurring at concentrations well above the physiological range) on pluripotency control are molecularly associated with the repression of p53, p21, and p16. Our findings establish that adequate intracellular NAD+ content is crucial for pluripotency; the distinct effects of NAM on pluripotency may be dependent not only on its metabolic advantage as a NAD+ precursor but also on the ability of NAM to enhance resistance to cellular stress. STEM Cells 2013;31:1121–1135

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