PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury

Charlotte Sarre; Rafael Contreras-Lopez; Nitirut Nernpermpisooth; Christian Barrere; Sarah Bahraoui; Claudia Terraza; Gautier Tejedor; Anne Vincent; Patricia Luz-Crawford; Kantapich Kongpol; Sarawut Kumphune; Christophe Piot; Joel Nargeot; Christian Jorgensen; Farida Djouad; Stéphanie Barrere-Lemaire

doi:10.1186/s13287-022-02840-0

PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury

Charlotte Sarre, Rafael Contreras-Lopez, Nitirut Nernpermpisooth, Christian Barrere, Sarah Bahraoui, Claudia Terraza, Gautier Tejedor, Anne Vincent, Patricia Luz-Crawford, Kantapich Kongpol, Sarawut Kumphune, Christophe Piot, Joel Nargeot, Christian Jorgensen, Farida Djouad, Stéphanie Barrere-Lemaire^*

^*Corresponding author for this work

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

Abstract

Background: Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives: The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. Methods and results: Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H₂O₂. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 10⁵ PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 10⁵ naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion: Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.

Original language	English
Article number	167
Pages (from-to)	167
Journal	Stem Cell Research and Therapy
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13287-022-02840-0
State	Published - Dec 2022

Bibliographical note

Funding Information:
This work was supported by Inserm, and the University of Montpellier (FD, SBL, CJ), by CNRS (SBL) as well as by Naresuan University (NN, SK). We also thank the “Fonds Marion et Elisabeth Brancher” for financial support of this project (CS PhD fellowship), la “Fondation pour la Recherche Médicale” (RCL, Post-doctoral fellow in France, no. SPF202005011936), the PHC program of Campus France (project number no. 44928QF; SK and SBL) as well the “Agence Nationale de Recherche” grant for the LabEx ICST ANR grant [ANR-11-LABX-0015; SBL, JN, AV, CB, CP] and PPAR-OA ANR grant [ANR-18-CE18-0010; FD, RCL, CJ].

Funding Information:
The authors wish to thank Laura Gallot for her technical assistance for ex vivo experiments and Carlota Fernandez Rico for building figures from Western-blots. The authors are grateful to Biocampus facilities and in particular, Steeve Thirard, Elodie Belan and Karim Mesbah for animal care (iExplore/RAM), Julio Mateos-Langerak and Chamrouen Sar for assistance with microscopy (MRI) as well as Nelly Pirot for histological preparations (RHEM).

Publisher Copyright:
© 2022, The Author(s).

Keywords

Apoptosis
Cardioprotection
Mesenchymal stem cells
Myocardial infarction
PPARβ/δ
Priming
Reperfusion injury

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10.1186/s13287-022-02840-0

Cite this

Sarre, C., Contreras-Lopez, R., Nernpermpisooth, N., Barrere, C., Bahraoui, S., Terraza, C., Tejedor, G., Vincent, A., Luz-Crawford, P., Kongpol, K., Kumphune, S., Piot, C., Nargeot, J., Jorgensen, C., Djouad, F., & Barrere-Lemaire, S. (2022). PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury. Stem Cell Research and Therapy, 13(1), 167. [167]. https://doi.org/10.1186/s13287-022-02840-0

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title = "PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury",

abstract = "Background: Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives: The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. Methods and results: Na{\"i}ve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus na{\"i}ve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 na{\"i}ve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion: Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.",

keywords = "Apoptosis, Cardioprotection, Mesenchymal stem cells, Myocardial infarction, PPARβ/δ, Priming, Reperfusion injury",

author = "Charlotte Sarre and Rafael Contreras-Lopez and Nitirut Nernpermpisooth and Christian Barrere and Sarah Bahraoui and Claudia Terraza and Gautier Tejedor and Anne Vincent and Patricia Luz-Crawford and Kantapich Kongpol and Sarawut Kumphune and Christophe Piot and Joel Nargeot and Christian Jorgensen and Farida Djouad and St{\'e}phanie Barrere-Lemaire",

note = "Funding Information: This work was supported by Inserm, and the University of Montpellier (FD, SBL, CJ), by CNRS (SBL) as well as by Naresuan University (NN, SK). We also thank the “Fonds Marion et Elisabeth Brancher” for financial support of this project (CS PhD fellowship), la “Fondation pour la Recherche M{\'e}dicale” (RCL, Post-doctoral fellow in France, no. SPF202005011936), the PHC program of Campus France (project number no. 44928QF; SK and SBL) as well the “Agence Nationale de Recherche” grant for the LabEx ICST ANR grant [ANR-11-LABX-0015; SBL, JN, AV, CB, CP] and PPAR-OA ANR grant [ANR-18-CE18-0010; FD, RCL, CJ]. Funding Information: The authors wish to thank Laura Gallot for her technical assistance for ex vivo experiments and Carlota Fernandez Rico for building figures from Western-blots. The authors are grateful to Biocampus facilities and in particular, Steeve Thirard, Elodie Belan and Karim Mesbah for animal care (iExplore/RAM), Julio Mateos-Langerak and Chamrouen Sar for assistance with microscopy (MRI) as well as Nelly Pirot for histological preparations (RHEM). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s13287-022-02840-0",

language = "English",

volume = "13",

pages = "167",

journal = "Stem Cell Research and Therapy",

issn = "1757-6512",

publisher = "BioMed Central Ltd.",

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Sarre, C, Contreras-Lopez, R, Nernpermpisooth, N, Barrere, C, Bahraoui, S, Terraza, C, Tejedor, G, Vincent, A, Luz-Crawford, P, Kongpol, K, Kumphune, S, Piot, C, Nargeot, J, Jorgensen, C, Djouad, F & Barrere-Lemaire, S 2022, 'PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury', Stem Cell Research and Therapy, vol. 13, no. 1, 167, pp. 167. https://doi.org/10.1186/s13287-022-02840-0

TY - JOUR

T1 - PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury

AU - Sarre, Charlotte

AU - Contreras-Lopez, Rafael

AU - Nernpermpisooth, Nitirut

AU - Barrere, Christian

AU - Bahraoui, Sarah

AU - Terraza, Claudia

AU - Tejedor, Gautier

AU - Vincent, Anne

AU - Luz-Crawford, Patricia

AU - Kongpol, Kantapich

AU - Kumphune, Sarawut

AU - Piot, Christophe

AU - Nargeot, Joel

AU - Jorgensen, Christian

AU - Djouad, Farida

AU - Barrere-Lemaire, Stéphanie

N1 - Funding Information: This work was supported by Inserm, and the University of Montpellier (FD, SBL, CJ), by CNRS (SBL) as well as by Naresuan University (NN, SK). We also thank the “Fonds Marion et Elisabeth Brancher” for financial support of this project (CS PhD fellowship), la “Fondation pour la Recherche Médicale” (RCL, Post-doctoral fellow in France, no. SPF202005011936), the PHC program of Campus France (project number no. 44928QF; SK and SBL) as well the “Agence Nationale de Recherche” grant for the LabEx ICST ANR grant [ANR-11-LABX-0015; SBL, JN, AV, CB, CP] and PPAR-OA ANR grant [ANR-18-CE18-0010; FD, RCL, CJ]. Funding Information: The authors wish to thank Laura Gallot for her technical assistance for ex vivo experiments and Carlota Fernandez Rico for building figures from Western-blots. The authors are grateful to Biocampus facilities and in particular, Steeve Thirard, Elodie Belan and Karim Mesbah for animal care (iExplore/RAM), Julio Mateos-Langerak and Chamrouen Sar for assistance with microscopy (MRI) as well as Nelly Pirot for histological preparations (RHEM). Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - Background: Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives: The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. Methods and results: Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion: Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.

AB - Background: Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives: The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. Methods and results: Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion: Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.

KW - Apoptosis

KW - Cardioprotection

KW - Mesenchymal stem cells

KW - Myocardial infarction

KW - PPARβ/δ

KW - Priming

KW - Reperfusion injury

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U2 - 10.1186/s13287-022-02840-0

DO - 10.1186/s13287-022-02840-0

M3 - Article

C2 - 35461240

AN - SCOPUS:85128780497

SN - 1757-6512

VL - 13

SP - 167

JO - Stem Cell Research and Therapy

JF - Stem Cell Research and Therapy

IS - 1

M1 - 167

ER -

PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia–reperfusion injury

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