Plasma endothelial cells-derived extracellular vesicles promote wound healing in diabetes through YAP and the PI3K/Akt/mTOR pathway

Extracellular vesicles are involved in skin wound healing and diabetes. After enrichment and identification, plasma endothelial cells-derived-extracellular vesicles were cocultured with skin fibroblasts or HaCaT. The gain-and loss-of functions were performed to measure fibroblast proliferation, senescence, and reactive oxygen species. Levels of senescence-related proteins, senescence-associated secretory phenotypes, vascular markers, YAP and the PI3K/Akt/mTOR pathway-related proteins were determined. Diabetic mice were induced to establish skin wound model. After endothelial cells-derived-extracellular vesicles were injected into skin wound modeling mice, skin wound healing was evaluated. Endothelial cells-derived-extracellular vesicles treatment enhanced fibroblast proliferation, and decreased senescence through the elevation of YAP nuclear translocation and activation the PI3K/Akt/mTOR pathway. YAP inhibition reversed the effect of plasma endothelial cells-derived-extracellular vesicles on fibroblast proliferation. Endothelial cells-derived-extracellular vesicles also promoted wound healing in diabetic mice, increased microvascular density, collagen deposition, macrophage infiltration and positive rates of vascular markers, and inhibited YAP phosphorylation and senescence. Plasma endothelial cells-derived-extracellular vesicles prevent fibroblast senescence and accelerate skin wound healing in diabetic mice by reducing YAP phosphorylation and activating the PI3K/Akt/mTOR pathway. This study may provide novel insights for skin disorders in diabetic mice.