Tissue engineering; Myocardial infarction; pre-clinical; Cell-based therapy; Ventricle remodeling
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Valentin Jérémy, Frobert Aurélien, Ajalbert Guillaume, Cook Stéphane, Giraud Marie-Noëlle (2016), Histological Quantification of Chronic Myocardial Infarct in Rats., in Journal of visualized experiments : JoVE
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Background. Ischemic heart disease is the most frequent causes of death in industrialized countries like Switzerland. The urgent need for new therapies fostered the development of strategies that focus on the recovery of the cardiac structure and function. Past decade, cell therapy has provided encouraging results. The treatment of the damaged myocardium relies on the administration of a large number of exogenous cells. Beneficial outcomes such as improved heart function and reduced remodeling may be mediated via the secretion of cytoprotective factors that stimulate revascularization, increase the recruitment of host progenitors cells and trigger in situ repair mechanisms. Nevertheless, the key players and pathways have not yet been identified. Further advance of cell therapy is, however, limited by several challenges. Poor retention of the administered cells represents a major issue. An interesting solution relies on the concomitant implantation of cells and exogenous matrix. Accordingly, we previously assessed the epicardial administration of different biografts in rodent model of myocardial infarction. We provided evidence that improved cell retention, increased and sustained therapeutic effects depend on the nature of the matrix. In light with this finding, we have identified fibrin glue associated with mesenchymal stem cell (MSC) as the most efficient biograft (named MFG) for cardiac function recovery. Last 8 years, we accumulated experimental successes for MI treatment with biografts. We have now reached an essential step: we have identified a very efficient way to regenerate the myocardium. Our efforts must be pursued in order to fine-tune the biograft-based therapy, characterize induced adaptive remodeling, identify repair mechanisms and translate these key findings obtained in animal models to a clinical reality.Aims. In the current proposal, we will pursue the ongoing project that was previously supported by the SNF, and expand our expertise in tissue engineering gained over the past 8 years into translational research. We therefore propose a clinically oriented investigation of MFG. We will first address two important shortcomings of cell therapies: (a) the time frame of cellular administration, and (b) the quality of the cells to be administrated. To answer this request, we will first compare the efficiency of MFG in acute and chronic myocardial infarction (MI) models (Specific aim 1). Secondly, we plan to evaluate the therapeutic efficiencies of MFG composed of cells isolated from either healthy or infarcted animals (Specific aim 2). Thirdly, we propose a molecular analysis to identify mechanism involved in myocardial regeneration and cardiac innervation remodeling (Specific aim 3). Finally, we aim to investigate MFG in large animal model of MI (Specific aim 4) and collect documents and data to prepare the clinical trial (Specific aim 5).Experimental design. To fulfill our aims, we will use different in vivo models. Briefly, acute and chronic MI will be performed in mice that undergo respectively a temporary (ischemia/reperfusion) or a permanent coronary ligation. Heart harvesting and mRNA isolation from remote and infarcted areas will allow identification of differential expression of markers of myocardial regeneration (with emphasis on genes involved innervation). Finally, the knowledge accumulated in both small animal models will be tested in a preclinical model (balloon-induced coronary occlusion and epicardial administration of MFG, minipig).