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

doi:10.1096/fj.201902232R

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

44 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 language	English
Pages (from-to)	8250-8264
Number of pages	15
Journal	FASEB Journal
Volume	34
Issue number	6
DOIs	https://doi.org/10.1096/fj.201902232R
State	Published - 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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10.1096/fj.201902232R

Cite this

Contreras-Lopez, R., Elizondo-Vega, R., Paredes, M. J., Luque-Campos, N., Torres, M. J., Tejedor, G., Vega-Letter, A. M., Figueroa-Valdés, A., Pradenas, C., Oyarce, K., Jorgensen, C., Khoury, M., Garcia-Robles, M. D. L. A., Altamirano, C., Djouad, F., & Luz Crawford, P. A. (2020). HIF1α-dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions. FASEB Journal, 34(6), 8250-8264. https://doi.org/10.1096/fj.201902232R

@article{f8c39d1ac7bb41279bbc9192b9607600,

title = "HIF1α-dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions",

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.",

keywords = "HIF1α, MSCs, glycolytic, immunomodulation, immunosuppression, metabolic reprogramming, metabolism",

author = "Rafael Contreras-Lopez and Roberto Elizondo-Vega and Paredes, {Maria Jose} and Noymar Luque-Campos and Torres, {Maria Jose} and Gautier Tejedor and Vega-Letter, {Ana Maria} and Aliosha Figueroa-Vald{\'e}s and Carolina Pradenas and Karina Oyarce and Christian Jorgensen and Maroun Khoury and Garcia-Robles, {Maria de los Angeles} and Claudia Altamirano and Farida Djouad and {Luz Crawford}, {Patricia Alejandra}",

note = "Funding Information: This work was supported by grants from the Chilean “Agencia Nacional de Investigaci{\'o}n y Desarrollo”:ANID: “Fondecyt Iniciaci{\'o}n” Nº11160929, “Fondecyt Iniciaci{\'o}n” Nº11190690, “Fondecyt Regular” Nº1170852, “Programa de apoyo a la formaci{\'o}n de redes internacionales” Nº180211 ; “Programa de Cooperaci{\'o}n Cient{\'i}fica 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: {\textquoteleft}Venida profesor extranjero,{\textquoteright} 2018,” Universidad de los Andes, Santiago, Chile. This project was also funded by the “Vicerrectoria de Investigaci{\'o}n y Desarrollo,” Proyecto VRID‐iniciaci{\'o}n 219.031.116‐INI and Proyecto VRID‐asociativo nº 218.031.113‐1 Universidad de Concepci{\'o}n, Concepci{\'o}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{\'e}t{\'e} Fran{\c c}aise de Rhumatologie (SFR). The authors would like to specially thank the staff of the platform SMARTY (part of “R{\'e}seau 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: {\textcopyright} 2020 Federation of American Societies for Experimental Biology",

year = "2020",

month = jun,

day = "1",

doi = "10.1096/fj.201902232R",

language = "English",

volume = "34",

pages = "8250--8264",

journal = "FASEB Journal",

issn = "0892-6638",

publisher = "FASEB",

number = "6",

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Contreras-Lopez, R, Elizondo-Vega, R, Paredes, MJ, Luque-Campos, N, Torres, MJ, Tejedor, G, Vega-Letter, AM, Figueroa-Valdés, A, Pradenas, C, Oyarce, K, Jorgensen, C, Khoury, M, Garcia-Robles, MDLA, Altamirano, C, Djouad, F & Luz Crawford, PA 2020, 'HIF1α-dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions', FASEB Journal, vol. 34, no. 6, pp. 8250-8264. https://doi.org/10.1096/fj.201902232R

TY - JOUR

T1 - HIF1α-dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions

AU - Contreras-Lopez, Rafael

AU - Elizondo-Vega, Roberto

AU - Paredes, Maria Jose

AU - Luque-Campos, Noymar

AU - Torres, Maria Jose

AU - Tejedor, Gautier

AU - Vega-Letter, Ana Maria

AU - Figueroa-Valdés, Aliosha

AU - Pradenas, Carolina

AU - Oyarce, Karina

AU - Jorgensen, Christian

AU - Khoury, Maroun

AU - Garcia-Robles, Maria de los Angeles

AU - Altamirano, Claudia

AU - Djouad, Farida

AU - Luz Crawford, Patricia Alejandra

N1 - 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

PY - 2020/6/1

Y1 - 2020/6/1

N2 - 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.

AB - 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.

KW - HIF1α

KW - MSCs

KW - glycolytic

KW - immunomodulation

KW - immunosuppression

KW - metabolic reprogramming

KW - metabolism

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U2 - 10.1096/fj.201902232R

DO - 10.1096/fj.201902232R

M3 - Article

C2 - 32333618

AN - SCOPUS:85084070345

SN - 0892-6638

VL - 34

SP - 8250

EP - 8264

JO - FASEB Journal

JF - FASEB Journal

IS - 6

ER -

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

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