Apoptotic Extracellular Vesicles Derived from Human Umbilical Vein Endothelial Cells Promote Skin Repair by Enhancing Angiogenesis: From Death to Regeneration

Abstract

The promotion of angiogenesis is an effective strategy for skin wound repair. While the transplantation of endothelial cells has shown promise in vascularization, the underlying mechanism remains unclear. Recent studies have suggested that transplanted cells undergo apoptosis in a short period and release apoptotic extracellular vesicles (ApoEVs) that may have therapeutic potential. Methods: In this study, we isolated ApoEVs from human umbilical vein endothelial cells (HUVECs) and characterized their properties. In vitro, we assessed the effects of ApoEVs on the proliferation, migration, and differentiation of endothelial cells and fibroblasts. In vivo, we investigated the therapeutic role of ApoEVs-AT in full-thickness skin wounds, evaluating wound closure rate, re-epithelialization, granulation tissue formation, vascularization, scar area, and collagen 3(Col3)/collagen 1(Col 1) ratio. Results: ApoEVs derived from HUVECs displayed typical characteristics. In vitro, ApoEVs significantly enhanced the proliferation, migration, tube formation, and expression of angiogenic-related genes in endothelial cells and slightly promoted the proliferation and migration of fibroblasts. In vivo, ApoEVs improved the wound closure rate, re-epithelialization, the formation of granulation tissue, and vascularization. Besides, ApoEVs reduced scar formation, accompanied by an increase in the Col 3/ Col 1 ratio. Conclusion: Given their abundant source and effectiveness, this study provided a novel approach for angiogenesis in tissue regeneration and deepened the understanding of from death to regeneration.

Hair follicle stem cells promote epidermal regeneration under expanded condition

“…Although the interplay of HFSCs and ECs has less been reported under expanded condition, they indeed play a crucial role in epidermal regeneration because tissue regeneration deeply relies on neovascularization and re-epithelization. For example, in angiogenesis, which is vital for skin barrier rebuilding ( Liu et al, 2024 ), Heidari reported that HF bulge cells increased vascularization in full-thickness wounds in mice instead of HF isthmus cells ( Heidari et al, 2016 ). In the study conducted by Babakhani, when HFSCs were administered around the periphery of the wound, it was observed that the wound area exhibited significant enhanced neovascularization, particularly notable on the 7th and 14th days following treatments, in comparison to other groups ( Babakhani et al, 2020 ).…”