Nicotinamide overcomes pluripotency deficits and reprogramming barriers

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Title
Nicotinamide overcomes pluripotency deficits and reprogramming barriers
Author(s)
Myung Jin SonMi Young SonBinna Seol; Min-Jeong Kim; Chae Wha Yoo; M K Han; Yee Sook Cho
Bibliographic Citation
Stem Cells, vol. 31, no. 6, pp. 1121-1135
Publication Year
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.
Keyword
Human embryonic stem cellHuman induced pluripotent stem cellNAD+NicotinamidePluripotencyReprogramming
ISSN
1066-5099
Publisher
Wiley
DOI
http://dx.doi.org/10.1002/stem.1368
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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