NAD^(+) salvage governs the immunosuppressive capacity of mesenchymal stem cells
作者机构：The Third Affiliated Hospital of Soochow UniversityInstitutes for Translational MedicineState Key Laboratory of Radiation Medicine and ProtectionSuzhou Medical College of Soochow UniversitySuzhouChina Department of Experimental Medicine and Biochemical SciencesTORUniversity of Rome“Tor Vergata”RomeItaly Laboratory Animal CenterSuzhou Medical College of Soochow UniversitySuzhouChina Shanghai Institute of Nutrition and HealthChinese Academy of SciencesShanghaiChina
出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)
年 卷 期：2023年第20卷第10期
页 面：1171-1185页
核心收录：
学科分类：1001[医学-基础医学(可授医学、理学学位)] 100102[医学-免疫学] 10[医学]
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)
主 题：Mesenchymal stem/stromal cells NAD^(+)metabolism Immunomodulation Glycolysis HIF-1a Succinate
摘 要：Mesenchymal stem/stromal cells(MSCs)possess robust immunoregulatory functions and are promising therapeutics for inflammatory *** capacity is not innate but is activated or‘licensed’by inflammatory *** licensing mechanism remains ***,we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory *** 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^(+) *** NAD^(+) synthesis was blocked by inhibiting or depleting NAMPT,the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly ***,when NAD^(+) metabolism in MSCs was perturbed,their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver *** analysis revealed that NAMPT-driven production of NAD^(+) was critical for the inflammatory cytokine-induced increase in glycolysis in ***,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 *** study demonstrated that unlike its proinflammatory role in immune cells,NAD^(+) metabolism governs the anti-inflammatory function of MSCs during inflammation.
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