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Yuan, Xuegang ; Liu, Yijun ; Bijonowski, Brent M. ; Tsai, Ang-Chen ; Fu, Qin ; Logan, Timothy M. ; Ma, Teng ; Li, Yan ( , Communications Biology)
Abstract Human mesenchymal stem cells (hMSCs) promote endogenous tissue regeneration and have become a promising candidate for cell therapy. However, in vitro culture expansion of hMSCs induces a rapid decline of stem cell properties through replicative senescence. Here, we characterize metabolic profiles of hMSCs during expansion. We show that alterations of cellular nicotinamide adenine dinucleotide (NAD + /NADH) redox balance and activity of the Sirtuin (Sirt) family enzymes regulate cellular senescence of hMSCs. Treatment with NAD + precursor nicotinamide increases the intracellular NAD + level and re-balances the NAD + /NADH ratio, with enhanced Sirt-1 activity in hMSCs at high passage, partially restores mitochondrial fitness and rejuvenates senescent hMSCs. By contrast, human fibroblasts exhibit limited senescence as their cellular NAD + /NADH balance is comparatively stable during expansion. These results indicate a potential metabolic and redox connection to replicative senescence in adult stem cells and identify NAD + as a metabolic regulator that distinguishes stem cells from mature cells. This study also suggests potential strategies to maintain cellular homeostasis of hMSCs in clinical applications.
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Tsai, Ang-Chen ; Jeske, Richard ; Chen, Xingchi ; Yuan, Xuegang ; Li, Yan ( , Frontiers in Bioengineering and Biotechnology)
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Song, Liqing ; Tsai, Ang-Chen ; Yuan, Xuegang ; Bejoy, Julie ; Sart, Sébastien ; Ma, Teng ; Li, Yan ( , Tissue Engineering Part A)