Epicardial extracellular vesicles modulate gene expression following ischemia-reperfusion injury in heart-on-a-chip.

The epicardium is an essential regulator of cardiac development, homeostasis, and injury, yet the composition and impacts of epicardial cell-secreted extracellular vesicles (EVs) remain incompletely understood. Here, we harness an epicardial Biowire platform integrating human stem cell derived epicardial cells with functional myocardium and apply transcriptomics to reveal enriched EV transport in tissues containing epicardial cells. Profiling epicardial-EVs identified key miRNAs and their conservation through stimulated epithelial-to-mesenchymal transition. Supplementation of epicardial-EVs to tissues undergoing ischemia-reperfusion injury influenced gene expression associated with reduction of extracellular matrix remodeling, fibroblast activation, and suppression of cell-ECM interactions. Correlation of EV-miRNAs with mRNA targets highlighted the role of miR-30d-5p, miR-9-5p, miR-16-5p, and the let-7 family in moderating deleterious fibrotic activation and matrix remodeling during myocardial injury in vitro.