The Role of Endothelial Cell-Derived Extracellular Vesicles in Modulating Fibroblast Function in Skin Wound Healing

An adequate wound healing response requires the coordination of intercellular signals between multiple cell types. After skin injury, endothelial cells and fibroblasts provisionally replace the site of injury with newly vascularized granulation tissue. Given the spatial and temporal overlap of these 2 cell types in the healing response, we hypothesize that endothelial cell-derived extracellular vesicles (ECEVs) could provide a communication pathway through which endothelial cells influence fibroblast behavior. In this study, we investigated the effects of ECEVs on fibroblast function both in vitro and in vivo through a murine skin wound healing model. Transcriptomic analysis showed that the uptake of ECEVs by fibroblasts altered functions and pathways relating to cell division, extracellular matrix organization, and fibrosis. This gene signature resulted from upregulation of the transcription factor ETV1, which enhanced fibroblast susceptibility to FGF2 found on ECEVs. This transcriptomic analysis was functionally corroborated through in vitro assays in which fibroblasts demonstrated enhanced proliferation, cell cycle progression, and altered extracellular matrix deposition after ECEV treatment. Administration of ECEVs to healing mouse wounds led to increased collagen density and fibroblast quantity in the wound bed of scar tissue. Our study highlights a previously undefined role for ECEVs in regulating fibroblast function during wound repair.