HGF Overexpression in Mesenchymal Stromal Cell-Based Cell Sheets Enhances Autophagy-Dependent Cytoprotection and Proliferation to Guard the Epicardial Mesothelium.

Epicardial mesothelial cells (EMCs), which form the epicardium, play a crucial role in cardiac homeostasis and repair. Upon damage, EMCs reactivate embryonic development programs, contributing to wound healing, progenitor cell amplification, and regulation of lymphangiogenesis, angiogenesis, and fibrosis. However, the mechanisms governing EMC activation and subsequent regulation remain poorly understood. We hypothesized that hepatocyte growth factor (HGF), a pleiotropic regulator of various cellular functions, could modulate EMC activity. To verify this hypothesis, we developed HGF-overexpressing mesenchymal stromal cell sheets (HGF-MSC CSs) and evaluated their effects on EMCs in vitro and in vivo. This study has revealed, for the first time, that EMCs express the c-Met (HGF receptor) on their surface and that both recombinant HGF and HGF-MSC CSs secretome cause c-Met phosphorylation, triggering downstream intracellular signaling. Our findings demonstrate that the HGF-MSC CSs secretome promotes cell survival under hypoxic conditions by modulating the level of autophagy. At the same time, HGF-MSC CSs stimulate EMC proliferation, promoting their amplification in the damage zone. These data demonstrate that HGF-MSC CSs can be considered a promising regulator of epicardial cell activity involved in heart repair after ischemic damage.