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 PPAR beta/delta (Peroxisome proliferator-activated receptors (3/6) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPAR beta/delta-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPAR beta/delta expression on MSC cardioprotective and anti-apoptotic properties has never been investigated." - "Objectives: The aim of this study was to investigate the role of PPAR beta/delta modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction." - "Methods and results: Naive MSC and MSC pharmacologically activated or inhibited for PPAR beta/delta 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 PPAR beta/delta agonist GW0742 versus naive MSC. In addition, PPAR beta/delta-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 x 10(5) PPAR beta/delta-primed MSC/heart provided the same cardioprotective efficiency than 7.5 x 10(5) naive 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, PPAR beta/delta inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects." - "Conclusion: Altogether these results revealed that PPAR beta/delta-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPAR beta/delta-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."