Abstract
Introduction: Myocardial infarction (MI) is the primary manifestation of cardiovascular events. Synthetic cardiac stromal cells (synCSCs) were shown to promote cardiac repair after MI. Minimally invasive delivery of synCSCs embedded in hyaluronic acid (HA) hydrogel via intrapericardial cavity (iPC) injections in a porcine model may provide a unique dataset for cardiac regeneration therapeutics. Hypothesis: Minimally invasive delivery of synCSCs via iPC injection will improve pig cardiac function and cardiomyocyte (CM) proliferation. Methods: A pig MI model was created using coronary balloon occlusion, and Yorkshire male pigs underwent video-assisted thoracoscopic surgery for iPC injections. Cardiac function studies were conducted using MRI to measure left ventricle ejection fraction (LVEF) and the infarct area. Histology and immunohistochemistry (IHC) analyses were performed to investigate CM proliferation. Single nucleus RNA-sequencing (snRNA-sq) analysis was performed to identify key gene features and phenotype changes that may be affected by the synCSC treatment. Results: The iPC injection of synCSCs embedded in HA hydrogel improves cardiac function, enhances cardiomyocyte proliferation, and induces phenotype alteration in the pig MI model. MRI analysis depicts significantly attenuated infarct size and improved LVEF at Day 28 in the synCSC group. Histology shows reduced fibrotic percentage and improved infarct wall thickness. IHC analysis shows a significant increase in cardiomyocyte proliferation. SnRNA-seq elucidates immature cardiomyocytes with higher proliferation gene features. Conclusion: The results show significant improvements in pig cardiac function and CM proliferation. Interestingly, immature cardiomyocytes of a different phenotype emerged in the therapeutic group. These findings provide an unprecedented dataset to facilitate the clinical translation of cardiac tissue regeneration therapeutics.
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