NAD+/NADH redox alterations reconfigure metabolism and rejuvenate senescent human mesenchymal stem cells in vitro

• Published in: Communications biology 2020-12, Vol.3 (1), p.774-774, Article 774
• Main Authors: Yuan, Xuegang, Liu, Yijun, Bijonowski, Brent M., Tsai, Ang-Chen, Fu, Qin, Logan, Timothy M., Ma, Teng, Li, Yan
• Format: Article
• Language: English
• Subjects: 101/58; 13/100; 13/106; 13/107; 13/31; 13/51; 14/34; 38/90; 631/61/2035; 631/61/2320; 631/80/509; 82/58; Adenine; Biomedical and Life Sciences; Cell culture; Cell therapy; Fibroblasts; Fitness; Homeostasis; Life Sciences; Mesenchymal stem cells; Metabolism; Mitochondria; NAD; NADH; Senescence; Stem cells
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-01514-y

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. Yuan et al. characterise metabolic profiles of human mesenchymal stem cells (hMSCs) during cell expansion in culture. They find that late passage hMSCs exhibit a NAD + /NADH redox cycle imbalance and that adding NAD + precursor nicotinamide restores mitochondrial fitness and cellular homeostasis in senescent hMSCs indicating a possible route to preserve hMSC homeostasis for therapeutic use.