PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties

R. A. Contreras-Lopez; R. Elizondo-Vega; M. J. Torres; A. M. Vega-Letter; N. Luque-Campos; M. J. Paredes-Martinez; C. Pradenas; G. Tejedor; K. Oyarce; M. Salgado; C. Jorgensen; Maroun Khoury; G. Kronke; M. A. Garcia-Robles; C. Altamirano; Patricia Alejandra Luz Crawford; F. Djouad

doi:10.1038/s41598-020-68347-x

PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties

R. A. Contreras-Lopez, R. Elizondo-Vega, M. J. Torres, A. M. Vega-Letter, N. Luque-Campos, M. J. Paredes-Martinez, C. Pradenas, G. Tejedor, K. Oyarce, M. Salgado, C. Jorgensen, Maroun Khoury, G. Kronke, M. A. Garcia-Robles, C. Altamirano, Patricia Alejandra Luz Crawford^*, F. Djouad

^*Corresponding author for this work

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

15 Scopus citations

Abstract

Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.

Original language	English
Article number	11423
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-68347-x
State	Published - 1 Dec 2020

Bibliographical note

Funding Information:
The authors would like to thank Dr Naomi Taylor for her help, advices and comments. This work was supported by grants from the Chilean National Commission for Scientific and Technological Investigation-CONICYT : "Fondecyt Iniciación" Nº11160929, "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; “Fond-ecyt Postdoctorado” Nº 3190462, “Proyecto FAI: “Venida profesor extranjero”, 2018”, Universidad de los Andes, Santiago, Chile, VRID-iniciacion (N°. 219.031.116-INI) and VRID-asociativo from Universidad de Concepcion (n°0.218.031.113-1). We also acknowledge for their financial support the Agence Nationale pour la Recherche (ANR-18-CE18-0010), Inserm, the University of Montpellier, ECOS-Sud (action ECOS n° C18S03) and la Fon-dation Arthritis.

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© 2020, The Author(s).

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Contreras-Lopez, R. A., Elizondo-Vega, R., Torres, M. J., Vega-Letter, A. M., Luque-Campos, N., Paredes-Martinez, M. J., Pradenas, C., Tejedor, G., Oyarce, K., Salgado, M., Jorgensen, C., Khoury, M., Kronke, G., Garcia-Robles, M. A., Altamirano, C., Luz Crawford, P. A., & Djouad, F. (2020). PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties. Scientific Reports, 10(1), Article 11423. https://doi.org/10.1038/s41598-020-68347-x

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title = "PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties",

abstract = "Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.",

author = "Contreras-Lopez, {R. A.} and R. Elizondo-Vega and Torres, {M. J.} and Vega-Letter, {A. M.} and N. Luque-Campos and Paredes-Martinez, {M. J.} and C. Pradenas and G. Tejedor and K. Oyarce and M. Salgado and C. Jorgensen and Maroun Khoury and G. Kronke and Garcia-Robles, {M. A.} and C. Altamirano and {Luz Crawford}, {Patricia Alejandra} and F. Djouad",

note = "Funding Information: The authors would like to thank Dr Naomi Taylor for her help, advices and comments. This work was supported by grants from the Chilean National Commission for Scientific and Technological Investigation-CONICYT : {"}Fondecyt Iniciaci{\'o}n{"} Nº11160929, {"}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; “Fond-ecyt Postdoctorado” Nº 3190462, “Proyecto FAI: “Venida profesor extranjero”, 2018”, Universidad de los Andes, Santiago, Chile, VRID-iniciacion (N°. 219.031.116-INI) and VRID-asociativo from Universidad de Concepcion (n°0.218.031.113-1). We also acknowledge for their financial support the Agence Nationale pour la Recherche (ANR-18-CE18-0010), Inserm, the University of Montpellier, ECOS-Sud (action ECOS n° C18S03) and la Fon-dation Arthritis. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41598-020-68347-x",

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Contreras-Lopez, RA, Elizondo-Vega, R, Torres, MJ, Vega-Letter, AM, Luque-Campos, N, Paredes-Martinez, MJ, Pradenas, C, Tejedor, G, Oyarce, K, Salgado, M, Jorgensen, C, Khoury, M, Kronke, G, Garcia-Robles, MA, Altamirano, C, Luz Crawford, PA & Djouad, F 2020, 'PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties', Scientific Reports, vol. 10, no. 1, 11423. https://doi.org/10.1038/s41598-020-68347-x

TY - JOUR

T1 - PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties

AU - Contreras-Lopez, R. A.

AU - Elizondo-Vega, R.

AU - Torres, M. J.

AU - Vega-Letter, A. M.

AU - Luque-Campos, N.

AU - Paredes-Martinez, M. J.

AU - Pradenas, C.

AU - Tejedor, G.

AU - Oyarce, K.

AU - Salgado, M.

AU - Jorgensen, C.

AU - Khoury, Maroun

AU - Kronke, G.

AU - Garcia-Robles, M. A.

AU - Altamirano, C.

AU - Luz Crawford, Patricia Alejandra

AU - Djouad, F.

N1 - Funding Information: The authors would like to thank Dr Naomi Taylor for her help, advices and comments. This work was supported by grants from the Chilean National Commission for Scientific and Technological Investigation-CONICYT : "Fondecyt Iniciación" Nº11160929, "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; “Fond-ecyt Postdoctorado” Nº 3190462, “Proyecto FAI: “Venida profesor extranjero”, 2018”, Universidad de los Andes, Santiago, Chile, VRID-iniciacion (N°. 219.031.116-INI) and VRID-asociativo from Universidad de Concepcion (n°0.218.031.113-1). We also acknowledge for their financial support the Agence Nationale pour la Recherche (ANR-18-CE18-0010), Inserm, the University of Montpellier, ECOS-Sud (action ECOS n° C18S03) and la Fon-dation Arthritis. Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.

AB - Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.

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U2 - 10.1038/s41598-020-68347-x

DO - 10.1038/s41598-020-68347-x

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AN - SCOPUS:85087765944

SN - 2045-2322

VL - 10

JO - Scientific Reports

JF - Scientific Reports

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M1 - 11423

ER -

PPARβ/δ-dependent MSC metabolism determines their immunoregulatory properties

Abstract

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