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

Rafael Contreras-Lopez, Roberto Elizondo-Vega, Noymar Luque-Campos, María José Torres, Carolina Pradenas, Gautier Tejedor, María José Paredes-Martínez, Ana María Vega-Letter, Mauricio Campos-Mora, Yandi Rigual-Gonzalez, Karina Oyarce, Magdiel Salgado, Christian Jorgensen, Maroun Khoury, María de los Ángeles Garcia-Robles, Claudia Altamirano, Farida Djouad, Patricia Luz-Crawford

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)445-460
Number of pages16
JournalTheranostics
Volume11
Issue number1
DOIs
StatePublished - 2021

Bibliographical note

Publisher Copyright:
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

© The author(s).

Keywords

  • AMPK activity
  • ATP synthase inhibition
  • Glycolytic metabolism
  • Immunotherapy
  • MSC

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