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Purpose: Each year, 15 million people suffer from a myocardial infarction and heart failure, resulting in one of the leading causes of death worldwide. Owing to the fact that the adult mammalian heart lacks a regenerative capacity, the ischemic cardiac muscle is replaced by scar tissue. While the mechanisms involved in fibrotic tissue formation are still elusive, the immune system is known to play a critical role. Therefore, modulating the immune response after cardiac injury is becoming a promising strategy to prevent scar formation and improve heart function after myocardial infarction.
Methods: Using a permanent left coronary artery ligation mouse model, we assessed the cardiac repair after myocardial infarction, in two conditions. The first condition involved depletion of a specific immune cell subtype with diphtheria toxin, using a genetically engineered model. On the other hand, the second condition involved the adoptive transfer of these cells in a clinically relevant manner, one day post ischemia, in wild type mice. The reparative cardiac capacity was assessed with echocardiography four weeks post ischemia, an angiogenesis assay, and Mason’s trichrome staining to assess the fibrotic area. To investigate the mechanisms of cardiac repair, we performed an EdU proliferation assay and a TUNEL survival assay on cardiomyocytes. Moreover, we performed flow cytometry and RNA sequencing on various immune cell subsets isolated from the infarcts to determine changes in the inflammatory response.
Results: Upon depletion of this particular immune cell subset, there was a significant increase in infarct size and a reduced left ventricular contractility (reduced ejection fraction and increased end diastolic volume), as evidenced with echocardiography. On the other hand, the adoptive transfer of the immune cell subset improved cardiac repair by reducing fibrosis and increasing the left ventricular contractility. This functional improvement was accompanied by enhanced angiogenesis in the infarct area, reduced cardiomyocyte cell death and moderately increased cardiomyocyte proliferation. In addition, the immune cells delivered by adoptive transfer accumulated at the site of cardiac injury and in secondary lymphoid organs post myocardial infarction. Mechanistically the pro-repair effect of this therapy was attributed to the differences in accumulation and the inflammatory phenotype of T cells and macrophages in the infarcts.
Conclusion: Taken together, we found that the delivery of this immune cell subset post ischemia diminished scar tissue formation by acting on multiple target populations and cellular processes, resulting in long-term improvement of cardiac function. This study demonstrates the potential of using this immune cell subset as a therapy for patients with myocardial infarction and potential heart failure.
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