NAD^(+) salvage governs the immunosuppressive capacity of mesenchymal stem cells  

作　　者：Jiankai Fang Pengbo Hou Shisong Liu Muqiu Zuo Zhanhong Liu Wangwang Chen Yuyi Han Yanan Li Tingting Wang Chao Feng Peishan Li Changshun Shao Yufang Shi 

机构地区：[1]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 [2]Department of Experimental Medicine and Biochemical Sciences,TOR,University of Rome“Tor Vergata”,Rome,Italy [3]Laboratory Animal Center,Suzhou Medical College of Soochow University,Suzhou,China [4]Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences,Shanghai,China

出　　处：《Cellular & Molecular Immunology》2023年第10期1171-1185,共15页中国免疫学杂志（英文版）

基　　金：supported by grants from the National Key R&D Program of China(2021YFA1100600 and 2022YFA0807300);the National Natural Science Foundation of China(82202032,81930085 and 32150710523);the Jiangsu Province International Joint Laboratory for Regenerative Medicine Fund and the Suzhou Foreign Academician Workstation Fund(SWY202202).

摘　　要：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.

关 键 词：Mesenchymal stem/stromal cells NAD^(+)metabolism IMMUNOMODULATION Glycolysis HIF-1A SUCCINATE 

分 类 号：R392[医药卫生—免疫学]