Abstract
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.
Highlights
Skin disorders are found in nearly one third of all diabetic populations and always occur before diagnosis, playing a considerable role in the preliminary recognition of diabetes [1]
CD63, CD81, tumor susceptibility gene 101 (TSG101) and vascular cell adhesion molecule 1 (VCAM-1) were significantly higher in plasma ED-Extracellular vesicles (EVs) than those in supernatant-negative control (S-NC), and glycoprotein VI (GPVI) was markedly low in both groups (Figure 1C)
Chronic wound in diabetes is a pivotal clinical issue, and the incidence is expected to elevate owing to an increased prevalence of diabetes [4]
Summary
Skin disorders are found in nearly one third of all diabetic populations and always occur before diagnosis, playing a considerable role in the preliminary recognition of diabetes [1]. Diabetic wounds impacted by insufficient angiogenesis, often result in non-healing ulcers, and decreased vascularity and capillary density; and owing to the high risk of chronic wound infection, they often end up with amputations [3, 4]. A literature review suggests that diabetes leads to skin wounds by modulating one or more biological processes of hemostasis, inflammation, proliferation and remodeling [6]. Chronic skin wounds feature with senescent fibroblasts, which lose their replication ability www.aging-us.com when preserving the metabolic functions [7]. In view of these points, we are encouraged to search for novel approaches to diabetic wound healing from the aspects of inflammation, senescence and proliferation of fibroblasts
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