학술논문
The ATP synthase inhibition induces an AMPK-dependent glycolytic switch of mesenchymal stem cells that enhances their immunotherapeutic potential.
Document Type
Academic Journal
Author
Contreras-Lopez R; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; IRMB, Université de Montpellier, INSERM, Montpellier, France.; Elizondo-Vega R; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.; Luque-Campos N; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Torres MJ; Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.; Pradenas C; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Tejedor G; IRMB, Université de Montpellier, INSERM, Montpellier, France.; Paredes-Martínez MJ; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Vega-Letter AM; Cells for Cells, Regenero, Las Condes, Santiago, Chile.; Laboratory of Nano-Regenerative Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Campos-Mora M; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Rigual-Gonzalez Y; Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.; Oyarce K; Facultad de Ciencias de la Salud, Universidad San Sebastián, Concepción, Chile.; Salgado M; Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.; Jorgensen C; IRMB, Université de Montpellier, INSERM, Montpellier, France.; Khoury M; Cells for Cells, Regenero, Las Condes, Santiago, Chile.; Laboratory of Nano-Regenerative Medicine, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.; Garcia-Robles MLÁ; Laboratorio de Biología Celular, Departamento de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.; Altamirano C; Escuela de Ingeniería Bioquímica, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.; Djouad F; IRMB, Université de Montpellier, INSERM, Montpellier, France.; Luz-Crawford P; Centro de Investigación e Innovación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
Source
Publisher: Ivyspring International Publisher Country of Publication: Australia NLM ID: 101552395 Publication Model: eCollection Cited Medium: Internet ISSN: 1838-7640 (Electronic) Linking ISSN: 18387640 NLM ISO Abbreviation: Theranostics Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
(© The author(s).)