Abstract
Myocardial infarction occurs after the abrupt occlusion of a coronary artery, leading to the massive death of cells due to the privation in oxygen and nutrient supply. The heart has a very low regenerative capacity with the inability to replace the dead contractile tissue. Thus, the formation of a fibrous scar to replace the dead cells will cause the loss of contractility of the myocardium, which may evolve towards heart failure in the patient. Cellular therapy relies on the exogenous supply of new cells that will help rebuilding the myocardium. Although Mesenchymal Stem Cells (MSCs) have shown strong therapeutic potential in preclinical animal models, clinical studies have shown inconsistent results in patients. Thus, the objective of this thesis project was to potentiate the effect of CSMs for the treatment of ischemia-reperfusion lesions during myocardial infarction. In a previous work, the team had shown that stimulation of a nuclear receptor could improve their therapeutic efficacy in an experimental arthritis model. The first part of the work was to set up the ex vivo model allowing to evaluate cell therapy in isolated hearts ex vivo. The results obtained using this ex vivo model show that the nuclear receptor identified as a candidate by the team is involved in the cardioprotection induced by MSCs against myocardial ischemia-reperfusion injury. Indeed, treating the myocardium during reperfusion with MSCs isolated from mice knockdowned for the gene encoding for this receptor does not protect the myocardium. Moreover, modulation of the receptor activity improves the resistance of MSCs to oxidative stress while increasing the number of cells engrafted in the myocardium at one hour of reperfusion. The mechanisms of action underlying the MSC-induced cardioprotection were studied. The results show that their anti-apoptotic properties on cardiac cells, both contractile and vascular, are increased when the target nuclear receptor is modulated by pharmacological agents. These very promising results suggest the development of an innovative therapy drug.