Uncovering the Regional and Cell Specific Bioactivity of Injectable Extracellular Matrix Biomaterials in Myocardial Infarction through Spatial and Single Nucleus Transcriptomics.

Myocardial infarction (MI) remains a global health concern. To mitigate MI pathophysiology, we previously investigated a pro-reparative decellularized extracellular matrix (ECM) hydrogel for treating subacute and chronic MI. 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 ECM biomaterials. ECM hydrogel subacute treatment induced cardiac resident macrophage preservation, fibroblast activation, and increased lymphatic, vasculature, smooth muscle and cardiomyocyte development as well as neurogenesis. Chronic treatment elicited macrophage polarization, cardiomyocyte and vasculature development, alongside fibroblast development. When comparing treatment timepoints, subacute administration had stronger immune modulation, while the chronic timepoint demonstrated higher cardiac development markers. Both subacute and chronic administration were associated with fibroblast activation and vasculature development. Thus, we elucidate undiscovered therapeutic targets of the ECM hydrogel, further demonstrating the potential of ECM biomaterials as an MI therapy.