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NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells

Cellular & Molecular Immunology volume 20, pages 1171–1185 (2023)Cite this article

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Abstract

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.

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Acknowledgements

This study was 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).

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Authors and Affiliations

  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

    Jiankai Fang, Pengbo Hou, Shisong Liu, Muqiu Zuo, Zhanhong Liu, Yuyi Han, Yanan Li, Tingting Wang, Chao Feng, Peishan Li, Changshun Shao & Yufang Shi

  2. Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome “Tor Vergata”, Rome, Italy

    Pengbo Hou, Zhanhong Liu, Yuyi Han, Yanan Li & Chao Feng

  3. Laboratory Animal Center, Suzhou Medical College of Soochow University, Suzhou, China

    Wangwang Chen

  4. Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China

    Yufang Shi

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  1. Jiankai Fang
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Contributions

JF: conception and design, collection and assembly of data, animal experiments, data analysis and interpretation, and manuscript writing. PH, SL, MZ, ZL, WC and CF: conception and design, data analysis and interpretation. YH, YL and TW: data analysis and interpretation. WC and CF: animal experiments. PL: data analysis and interpretation. CS and YS: conception and design, manuscript writing, administrative support and financial support.

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Correspondence to Changshun Shao or Yufang Shi.

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Fang, J., Hou, P., Liu, S. et al. NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells. Cell Mol Immunol 20, 1171–1185 (2023). https://doi.org/10.1038/s41423-023-01073-2

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