首页|NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells
NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells
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Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders.This capacity is not innate but is activated or'licensed'by inflammatory cytokines.The licensing mechanism remains unclear.Here,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity.In response to stimulation by inflammatory cytokines,MSCs exhibited a dramatic increase in the consumption of glucose,which was accompanied by an enhanced use of nicotinamide adenine dinucleotide(NAD+)and increased expression of nicotinamide phosphoribosyltransferase(NAMPT),a central enzyme in the salvage pathway for NAD+production.When NAD+synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated.Consequently,when NAD+metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury.Further analysis revealed that NAMPT-driven production of NAD+was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs.Furthermore,the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle,which led to hypoxia-inducible factor 1α(HIF-1α)stabilization and subsequently increased the transcription of key glycolytic genes,thereby persistently maintaining glycolytic flux.This study demonstrated that unlike its proinflammatory role in immune cells,NAD+metabolism governs the anti-inflammatory function of MSCs during inflammation.
The Third Affiliated Hospital of Soochow University,Institutes for Translational Medicine,State Key Laboratory of Radiation Medicine and Protection,Suzhou Medical College of Soochow University,Suzhou,China
Department of Experimental Medicine and Biochemical Sciences,TOR,University of Rome"Tor Vergata",Rome,Italy
Laboratory Animal Center,Suzhou Medical College of Soochow University,Suzhou,China
Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai,China
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National Key R&D Program of ChinaNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaJiangsu Province International Joint Laboratory for Regenerative Medicine Fund and the Suzhou Foreign Academician Workstatio
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