Inhibition of Ferroptosis by Adipose Stem Cell-Derived Apoptotic Vesicles Enhances Angiogenesis and Accelerates Diabetic Wound Healing.

PURPOSE: Impaired angiogenesis is a critical challenge in diabetic wound healing. While apoptotic derivatives of stem cells hold promise for regenerative therapy, their role in modulating angiogenesis within the diabetic wound microenvironment remains underexplored. This study aims to investigate whether adipose stem cell-derived apoptotic vesicles (ASCs-apoVs) promote angiogenesis and accelerate diabetic wound healing by inhibiting endothelial cell ferroptosis. METHODS: Diabetic mice model was established by feeding with high-fat diet (HFD) for 3 months followed by full-thickness skin wound preparation. Adipose stem cells (ASCs) isolated from adipose tissue were treated with staurosporine (STS) to induce apoptosis in vitro. Apoptotic vesicles (apoVs) were isolated by differential centrifugation, characterized using TEM, dynamic light scattering (DLS), and Western blot, and applied topically to diabetic wounds. The therapeutic effects of apoVs on wound healing efficiency, vascularization level and endothelial cell ferroptosis were evaluated. RESULTS: HFD-induced diabetes promoted lipid peroxidation (4HNE accumulation) and ferroptosis in endothelial cells (ECs), leading to reduced CD31(+) and vWf(+) vessel density and delayed wound closure. In vitro diabetic endothelial cell models confirmed increased lipid peroxidation and ferroptosis, which compromised the proliferation, migration and tube formation capacities of ECs. ASCs-apoVs, characterized by typical extracellular vesicle (EV) morphology and apoptotic markers, significantly inhibited lipid peroxidation and ferroptosis of ECs, thereby promoting angiogenesis and accelerating diabetic wound healing. CONCLUSION: Ferroptosis of endothelial cells contributes to impaired vascularization in diabetic wounds. ApoVs represent a promising cell-free therapeutic approach to mitigate ferroptosis, restore endothelial function and promote angiogenesis, offering a potential strategy for diabetic wound management.