Regional and cell specific bioactivity of injectable extracellular matrix biomaterials in myocardial infarction

Myocardial infarction (MI) remains a global health concern. To mitigate subacute and chronic MI pathophysiology, we previously investigated a pro-reparative decellularized extracellular matrix hydrogel. Despite increasing interest in biomaterial scaffolds, single cell and spatially resolved transcriptomics have not been used to probe their therapeutic activity in the heart. Here, we utilize spatial transcriptomics and single nucleus RNA sequencing to delineate the regional and cell-specific bioactivity of extracellular matrix biomaterials. Extracellular matrix hydrogel subacute treatment in female rats induces cardiac resident macrophage preservation, fibroblast activation, and increased lymphatic, vasculature, smooth muscle, and cardiomyocyte development as well as neurogenesis. Chronic treatment in female rats elicits macrophage polarization, neurogenesis, and development of cardiomyocytes, endothelial cells, and fibroblasts. When comparing treatment timepoints, subacute administration has stronger immune modulation, while chronic administration demonstrates higher cardiac development markers. Both subacute and chronic administration are associated with fibroblast activation and vasculature development. Thus, we elucidate undiscovered therapeutic targets of an injectable extracellular matrix hydrogel, further demonstrating the potential of these biomaterials as an MI therapy.