The ATP synthase inhibition induces an AMPK-dependent glycolytic switch of mesenchymal stem cells that enhances their immunotherapeutic potential

• Published in: Theranostics Vol. 11; no. 1; pp. 445 - 460
• Main Authors: Contreras-Lopez, Rafael, Elizondo-Vega, Roberto, Luque-Campos, Noymar, Torres, María José, Pradenas, Carolina, Tejedor, Gautier, Paredes-Martínez, María José, Vega-Letter, Ana María, Campos-Mora, Mauricio, Rigual-Gonzalez, Yandi, Oyarce, Karina, Salgado, Magdiel, Jorgensen, Christian, Khoury, Maroun, Garcia-Robles, María de Los Ángeles, Altamirano, Claudia, Djouad, Farida, Luz-Crawford, Patricia
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2021; Ivyspring International Publisher
• Subjects: AMP-Activated Protein Kinases; Animals; Antibodies; Antimetabolites; CD4-Positive T-Lymphocytes; Cell growth; Deoxyglucose; Disease Models, Animal; Enzyme Inhibitors; Flow cytometry; Glucose; Glycolysis; Graft versus host disease; Graft vs Host Disease; Humans; Hypersensitivity, Delayed; Hypoxia; Immunotherapy; Kinases; Laboratory animals; Lactic Acid; Life Sciences; Lymphocytes; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Metabolism; Mice; Mitochondrial Proton-Translocating ATPases; Monocarboxylic Acid Transporters; Oligomycins; Oxidative Phosphorylation; Oxygen Consumption; Phosphorylation; Research Paper; Chile; United States > US; Germany; AMPK activity; glycolytic metabolism; MSC; ATP synthase inhibition; immunotherapy
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.51631

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. 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 using co-culture experiments with pro-inflammatory T cells and with the Delayed-Type Hypersensitivity (DTH) and the Graph versus Host Disease (GVHD) murine models. We found that the oligomycin-mediated pro-glycolytic switch of MSC significantly enhanced their immunosuppressive properties . Conversely, glycolysis inhibition using 2DG significantly reduced MSC immunoregulatory effects. Moreover, , 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. 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.