HIF1α-dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions

Rafael Contreras-Lopez, Roberto Elizondo-Vega, Maria Jose Paredes, Noymar Luque-Campos, Maria Jose Torres, Gautier Tejedor, Ana Maria Vega-Letter, Aliosha Figueroa-Valdés, Carolina Pradenas, Karina Oyarce, Christian Jorgensen, Maroun Khoury, Maria de los Angeles Garcia-Robles, Claudia Altamirano, Farida Djouad, Patricia Alejandra Luz Crawford

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Hypoxia-inducible factor 1 α (HIF1α), a regulator of metabolic change, is required for the survival and differentiation potential of mesenchymal stem/stromal cells (MSC). Its role in MSC immunoregulatory activity, however, has not been completely elucidated. In the present study, we evaluate the role of HIF1α on MSC immunosuppressive potential. We show that HIF1α silencing in MSC decreases their inhibitory potential on Th1 and Th17 cell generation and limits their capacity to generate regulatory T cells. This reduced immunosuppressive potential of MSC is associated with a metabolic switch from glycolysis to OXPHOS and a reduced capacity to express or produce some immunosuppressive mediators including Intercellular Adhesion Molecule (ICAM), IL-6, and nitric oxide (NO). Moreover, using the Delayed-Type Hypersensitivity murine model (DTH), we confirm, in vivo, the critical role of HIF1α on MSC immunosuppressive effect. Indeed, we show that HIF1α silencing impairs MSC capacity to reduce inflammation and inhibit the generation of pro-inflammatory T cells. This study reveals the pivotal role of HIF1α on MSC immunosuppressive activity through the regulation of their metabolic status and identifies HIF1α as a novel mediator of MSC immunotherapeutic potential.

Original languageEnglish
Pages (from-to)8250-8264
Number of pages15
JournalFASEB Journal
Volume34
Issue number6
DOIs
StatePublished - 1 Jun 2020

Bibliographical note

Funding Information:
This work was supported by grants from the Chilean “Agencia Nacional de Investigación y Desarrollo”:ANID: “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, “Proyecto FAI: ‘Venida profesor extranjero,’ 2018,” Universidad de los Andes, Santiago, Chile. This project was also funded by the “Vicerrectoria de Investigación y Desarrollo,” Proyecto VRID‐iniciación 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), the national infrastructure: “ECELLFRANCE: Development of a national adult mesenchymal stem cell‐based therapy platform” (ANR‐11‐INSB‐005), Inserm, the University of Montpellier, the Société Française de Rhumatologie (SFR). The authors would like to specially thank the staff of the platform SMARTY (part of “Réseau des Animaleries de Montpellier, France”) for expert care of the mice colonies.

Funding Information:
This work was supported by grants from the Chilean ?Agencia Nacional de Investigaci?n y Desarrollo?:ANID: ?Fondecyt Iniciaci?n? N?11160929, ?Fondecyt Iniciaci?n? N?11190690, ?Fondecyt Regular? N?1170852, ?Programa de apoyo a la formaci?n de redes internacionales? N?180211; ?Programa de Cooperaci?n Cient?fica ECOS-CONICYT? N? PC18S04-ECOS180032; Beca Doctorado Nacional 2014 RC-L N? 21141173; ?Beca Doctorado Nacional? 2019 NL-C N? 2191997; ?Fondecyt Postdoctorado? N? 3190462, ?Proyecto FAI: ?Venida profesor extranjero,? 2018,? Universidad de los Andes, Santiago, Chile. This project was also funded by the ?Vicerrectoria de Investigaci?n y Desarrollo,? Proyecto VRID-iniciaci?n 219.031.116-INI and Proyecto VRID-asociativo n? 218.031.113-1 Universidad de Concepci?n, Concepci?n, Chile. We also acknowledge the Agence Nationale pour la Recherche (ANR) for the financial support with the project ?PPAROA? (ANR-18-CE18-0010-02), the national infrastructure: ?ECELLFRANCE: Development of a national adult mesenchymal stem cell-based therapy platform? (ANR-11-INSB-005), Inserm, the University of Montpellier, the Soci?t? Fran?aise de Rhumatologie (SFR). The authors would like to specially thank the staff of the platform SMARTY (part of ?R?seau des Animaleries de Montpellier, France?) for expert care of the mice colonies.

Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology

Keywords

  • HIF1α
  • MSCs
  • glycolytic
  • immunomodulation
  • immunosuppression
  • metabolic reprogramming
  • metabolism

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