Abstract
Abstract Background Mesenchymal stem/stromal cells (MSCs) render potential therapies for multiple ischemic diseases. However, in vitro expansion of MSCs before application leads to a metabolic switch from glycolysis to oxidative phosphorylation, drastically impairing their proliferative and therapeutic capacities. Purpose Here we aim to identify the role of SIRT5, a master metabolic regulator, in culture expansion of adipose-derived MSCs (ADMSCs). Methods SIRT5 deficiencyADMSCs was obtained from Sirt5−/− mice and their metabolic pattern and proliferation capacity were tested during in vitro expansion. Hind limb ischemic model was established to evaluated the therapeutic function of Sirt5−/−ADMSCs. Results SIRT5 protein level was upregulated in ADMCSs undergoing culture expansion. Sirt5−/−ADMSCs during in vitro expansion exhibited higher proliferation rate, delayed senescence and enhanced antioxidant capacity. SIRT5 deficiency induced hypersuccinylation of metabolic-related proteins, leading to attenuated mitochondrial respiration with elevated glycolysis and pentose phosphate pathway. Furthermore, lowering succinylation level by glycine treatment reversed the altered metabolism and enhanced proliferation of Sirt5−/−ADMSCs. In mice hind limb ischemic model, SIRT5−/−ADMSCs treatment achieved better blood flow recovery and angiogenesis compared to WT ADMSCs treatment. Conclusion We reveal that SIRT5 is a key regulator of ADMSCs undergoing in vitro culture. Ablation of SIRT5 leads to reversed metabolic pattern, enhanced proliferative capacity and improved therapeutic outcomes. Our data provide a potential target for enhancing MSC functional properties during bio-manufacturing in future MSC therapy. Such work may not only benefit MSC cell therapy, but could extent to a wide variety of other stem cells that share similar metabolic pattern. Graphic Abstract Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Major Research Plan of the National Natural Science Foundation of China. National Science Fund for Distinguished Young Scholars.
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