Objectives: Mesenchymal Stem/Stromal Cells (MSC) are promising therapeutic tools for inflammatory diseases due to their potent immunoregulatory capacities. Their suppressive activity mainly depends on inflammatory cues that have been recently associated with changes in MSC bioenergetic status towards a glycolytic metabolism. However, the molecular mechanisms behind this metabolic reprogramming and its impact on MSC therapeutic properties have not been investigated. Methods: Human and murine-derived MSC were metabolically reprogramed using pro-inflammatory cytokines, an inhibitor of ATP synthase (oligomycin), or 2-deoxy-D-glucose (2DG). The immunosuppressive activity of these cells was tested in vitro using co-culture experiments with pro-inflammatory T cells and in vivo with the Delayed-Type Hypersensitivity (DTH) and the Graph versus Host Disease (GVHD) murine models. Results: We found that the oligomycin-mediated pro-glycolytic switch of MSC significantly enhanced their immunosuppressive properties in vitro. Conversely, glycolysis inhibition using 2DG significantly reduced MSC immunoregulatory effects. Moreover, in vivo, MSC glycolytic reprogramming significantly increased their therapeutic benefit in the DTH and GVHD mouse models. Finally, we demonstrated that the MSC glycolytic switch effect partly depends on the activation of the AMPK signaling pathway. Conclusion: Altogether, our findings show that AMPK-dependent glycolytic reprogramming of MSC using an ATP synthase inhibitor contributes to their immunosuppressive and therapeutic functions, and suggest that pro-glycolytic drugs might be used to improve MSC-based therapy.
Nota bibliográficaFunding Information:
The authors would like to thank Dr Naomi Taylor for her help, advices and comments. This work was supported by grants from the Chilean National Commission for Scientific and Technological Investigation-CONICYT: “Fondecyt Iniciación” Nº11160929, “Fondecyt Iniciación” Nº11190690 “Fondecyt Regular” Nº1170852, "Programa de apoyo a la formación de redes internacionales" Nº180211; “Programa de Cooperación Científica ECOS-CONICYT” Nº PC18S04-ECOS180032; Beca Doctorado Nacional 2014 RC-L Nº 21141173; “Beca Doctorado Nacional” 2019 NL-C Nº 2191997; “Fondecyt Postdoctorado” Nº 3190462 and “Proyecto FAI: “Venida profesor extranjero”, 2018”, Universidad de los Andes, Santiago, Chile. Proyecto VRID-iniciación Nº 219.031.116-INI and Proyecto VRID asociativo Nº 218.031.113-1, Universidad de Concepción, Concepción, Chile. We also acknowledge the Agence Nationale pour la Recherche (ANR) for the financial support with the project “PPAROA” (ANR-18-CE18-0010-02), Inserm, the University of Montpellier and the “Fondation Arthritis”. The authors would like to specially thank to Macarena Ocaña and Claudia Rubí (C4C-Regenero Animal Facility) for technical expertise and assistance in the in vivo experiments, and the staff of the platform SMARTY (part of “Réseau des Animaleries de Montpellier, France”) for expert care of mice.
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© The author(s).