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

冠状动脉急性闭塞导致局部心肌缺血，从而导致心肌细胞死亡。这引起广泛的炎症反应，在心肌梗死后的第一天涉及中性粒细胞和促炎巨噬细胞。随后，抗炎巨噬细胞在心脏中积累，这对协调受损心肌的愈合至关重要。血管生成和纤维化瘢痕的形成是后期稳定受损心肌壁的关键过程。最近通过新的单细胞测序方法获得的数据表明，与之前的假设相反，中性粒细胞、巨噬细胞和成纤维细胞表现出高度的可塑性，导致心肌梗死后心脏中出现多种亚群。然而，它们的功能影响仍然难以捉摸。我们项目的目的是通过使用单细胞测序技术来研究小鼠心肌梗死模型中中性粒细胞、巨噬细胞和成纤维细胞亚群的异质性。为此，我们计划分析基础条件下以及心肌梗死后第1、3和7天的细胞群。我们合作项目的一个重要目标是分析我们在CRC1116项目中确定的三种心脏保护原理的调节作用，即Igf1的应用、棕色脂肪组织（BAT）的激活和细胞外基质通过Rhamm受体结合透明质酸的过表达的作用。通过对单细胞测序数据的生物信息学分析，我们期望深入了解成纤维细胞、中性粒细胞和巨噬细胞的细胞异质性，以及由于所描述的心脏保护干预而导致的它们的定量、定性和动态调节。基于鉴定细胞群表达模式的成对受体配体分析将为心肌梗死后中性粒细胞、巨噬细胞和成纤维细胞之间的细胞间通讯以及它们在心脏保护条件下的调节提供新的模型。由于诱导AMI的实验方案、细胞分离和分选在CRC1116中是标准化的，我们期望对数据的比较分析将允许识别共同的特定细胞群和信号通路，这可能解释保护性干预的心脏保护作用。当然，这些细胞和/或信号通路可能代表了开发特定治疗干预措施的新的可能靶点。

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.