Résumé
Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in acute myocardial infarction (AMI) due to their pleiotropic properties. Despite promising results in animal studies and their safety and efficacy in phase I/II trials, inconsistencies have been reported in phase III trials. Recently, we have shown in a mouse model of ischemia-reperfusion (IR) that PPARβ/δ preconditioning of MSC allows to improve their therapeutic efficacy.ObjectiveThe present study aims at investigating the role of PPARβ/δ activation on human MSC to enhance their therapeutic properties in myocardial IR injury in a way of clinical translation.Method: Cultured human adipose-derived MSC (ASC) were pretreated with 1 µM of PPARβ/δ agonist GW0742 (ASC-Pr). ASC or ASC-Pr were challenged with various stresses including simulated oxidative and freezing/thawing stresses. Apoptosis was quantified in stressed ASC or ASC-Pr. The therapeutic properties of ASC and ASC-Pr were evaluated in vitro by co-culturing them with H9c2 cardiomyoblasts and Eahy926 human endothelial cells challenged with H2O2. Ex vivo and in vivo evaluation was obtained using mouse models of myocardial ischemia-reperfusion after cell administration during reperfusion and infarct size was measured using the TTC method.Results: Apoptosis was decreased in ASC-Pr vs naïve ASC upon H2O2- or freezing/thawing induced stress showing an increased resistance of primed ASC. We observed also for ASC-Pr a more potent anti-apoptotic effect on both cardiomyocytes and endothelial cells in vitro than naïve ASC. Ex vivo, PPARβ/δ preconditioning allowed to reveal and increase the cardioprotective effect of naïve ASC perfused at a suboptimal dose (p<0.05; n=12 in each group). In vivo, ASC priming allowed to increase the cardioprotective effect not present in naïve condition (p=ns IR versus ASC and p*<0.05 IR vs ASC-Pr.Conclusion: PPARβ/δ preconditioning enhanced the ASC resistance to apoptosis. The efficacy of ASC-based therapy was increased using this preconditioning protocol by increasing their anti-apoptotic effects on cardiomyocytes and endothelial cells. These results are of major interest to improve ASC efficacy for the cardioprotection of the myocardium in AMI patients.