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.
Bibliographical noteFunding 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].
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).
© 2022, The Author(s).
- Mesenchymal stem cells
- Myocardial infarction
- Reperfusion injury