A novel role for endothelial cell-derived extracellular vesicles in modulating fibroblast behavior in skin wound healing

Summary: Abstract Body: An adequate wound healing response requires the coordination of intercellular signals between multiple cell types. Following 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 two cell types in the healing response, we hypothesize that they likely communicate through the release of endothelial cell-derived extracellular vesicles (ECEVs) that influence fibroblast behavior. Thus, 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. Uptake of ECEVs by fibroblasts was shown to alter functions and pathways relating to cell division, ECM organization, and fibrosis. This was functionally corroborated through in vitro assays, in which fibroblasts demonstrated enhanced proliferation, migration, cell cycle progression, collagen contraction, and altered ECM deposition following ECEV treatment. In vivo administration of ECEVs to healing mouse wounds led to greater collagen density and an upregulated fibroblast quantity in the wound bed of scar tissue. Our study highlights a novel role for ECEVs in shifting fibroblasts towards a potentially pro-fibrotic phenotype in the context of wound repair and tissue fibrosis. Heidi Yuan¹, Anna M. Salapatas², Trevor Leonardo², Chen Han¹, Bhavya Vegesna², Mateusz Wietecha³, Lin Chen², Sriram Ravindran³, Luisa DiPietro⁴ 1. Medical Scientist Training Program, University of Illinois Chicago College of Medicine, Chicago, IL, United States. 2. Center for Wound Healing and Tissue Regeneration, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States. 3. Department of Oral Biology, University of Illinois Chicago, Chicago, IL, United States. 4. Department of Periodontics, University of Illinois Chicago, Chicago, IL, United States. Stem Cell Biology, Tissue Regeneration and Wound Healing