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Theranostics 2021; 11(1):445-460. doi:10.7150/thno.51631 This issue Cite

Research Paper

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

Rafael Contreras-Lopez^1,2#, Roberto Elizondo-Vega^1,3#, Noymar Luque-Campos¹, María José Torres⁴, Carolina Pradenas¹, Gautier Tejedor², María José Paredes-Martínez¹, Ana María Vega-Letter^5,6, Mauricio Campos-Mora¹, Yandi Rigual-Gonzalez⁴, Karina Oyarce⁷, Magdiel Salgado³, Christian Jorgensen², Maroun Khoury^5,6, María de los Ángeles Garcia-Robles³, Claudia Altamirano⁴, Farida Djouad^2✉, Patricia Luz-Crawford^1✉

1. Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
2. IRMB, Université de Montpellier, INSERM, Montpellier, France.
3. Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
4. Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.
5. Cells for Cells, Regenero, Las Condes, Santiago, Chile.
6. Laboratory of Nano-Regenerative Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
7. Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile.
#These authors contributed equally to this work.

✉ Corresponding authors: Equally contributing co-corresponding authors. Patricia Luz-Crawford: Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile. Tel: 56 (2) 26181481; E-mail: pluzcl; Farida Djouad: Inserm U 1183, IRMB, Hôpital Saint-Eloi, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France. Tel: 33 (0) 4 67 33 04 75; E-mail: farida.djouadfr. More

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.

Keywords: MSC, ATP synthase inhibition, glycolytic metabolism, AMPK activity, immunotherapy

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