Modulation of the immune cell/ fibroblast response in acute myocardial infarction

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The acute occlusion of a coronary artery results in a local myocardial ischaemia which leads to cardiomyocyte death. This induces an extensive inflammatory response, which in the first days post MI involves neutrophils and pro-inflammator macrophages. Subsequently, anti-inflammatory macrophages accumulate in the heart, which are critically involved in orchestrating the healing of the damaged myocardium. Angiogensis and formation of a fibrotic scar are key processes which eventually stabalize the damaged myocardial wall in a later phase. Recent data obtained by novel single cell sequencing methods have demonstrated, that in contrast to earlier assumptions neutrophils, macrophages, and fibroblasts show a high degree of plasticity, giving rise to manifold subpopulations appearing in the heart after myocardial infarction. Their functional impact, however, remains elusive.It is the aim of our project to investigate by the use of single cell sequencing techniques the heterogeneity of neutrophil, macrophage, and fibroblast sub-populations in a murine model of myocardial infarction. To this end, we plan to analyse the cell populations under basal conditions as well as on day 1, 3, and 7 post MI. An important aim of our collaborative project is the analysis of the modulatory effects of three cardioprotective principles which we identified in our CRC1116 projects, namely the application of Igf1, the activation of brown adipose tissue (BAT) and the effect of the extracellular matrix by overexpression of the Rhamm receptor binding hyaluronic acid. By bioinformatic analysis of single cell sequncing data we expect a deep insight into the cellular heterogeneity of fibroblasts, neutrophils and macrophages, and their quantitative, qualitative, and dynamic modulataion due to the described cardiprotective interventions. Pairwise Receptor-Ligand analysis based on the expression patterns of the identified cell populations will provide new models of cell-cell communication between neutrophils, macropahges, and fibroblasts occuring after MI, as well as their modulation under cardioprotective conditions. Since the experimental protocols for induction of AMI, cell isolation and sorting are standardized in CRC1116, we expect that a comparative analysis of the data will allow the identification of common specific cell populations and signalling pathways which may explain the cardioprotective effects of the protective interventions. These cells and/or signalling pathways may represent, of course, novel possible targets for the development of specific therapeutic interventions.