Zhang Jingyi, Kuang Jinxin, Gong Shengkai, Wang Hanzhe, Ding Feng, Zhao Lu, Shi Lele, Liu Shiyu, Zhao Yimin, Liu Jiani, Dou Geng
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, People's Republic of China.
Int J Nanomedicine. 2025 Aug 6;20:9753-9770. doi: 10.2147/IJN.S527475. eCollection 2025.
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.
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.
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.
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.
血管生成受损是糖尿病伤口愈合中的一项关键挑战。虽然干细胞的凋亡衍生物有望用于再生治疗，但其在糖尿病伤口微环境中调节血管生成的作用仍未得到充分研究。本研究旨在探讨脂肪干细胞来源的凋亡小泡（ASCs-apoVs）是否通过抑制内皮细胞铁死亡来促进血管生成并加速糖尿病伤口愈合。
通过喂食高脂饮食（HFD）3个月建立糖尿病小鼠模型，随后制备全层皮肤伤口。从脂肪组织中分离出的脂肪干细胞（ASCs）在体外用星形孢菌素（STS）处理以诱导凋亡。通过差速离心分离凋亡小泡（apoVs），使用透射电子显微镜（TEM）、动态光散射（DLS）和蛋白质免疫印迹法进行表征，并局部应用于糖尿病伤口。评估apoVs对伤口愈合效率、血管化水平和内皮细胞铁死亡的治疗效果。
高脂饮食诱导的糖尿病促进了内皮细胞（ECs）中的脂质过氧化（4-HNE积累）和铁死亡，导致CD31和vWf血管密度降低以及伤口闭合延迟。体外糖尿病内皮细胞模型证实脂质过氧化和铁死亡增加，这损害了内皮细胞的增殖、迁移和管腔形成能力。具有典型细胞外囊泡（EV）形态和凋亡标志物特征的ASCs-apoVs显著抑制了内皮细胞的脂质过氧化和铁死亡，从而促进血管生成并加速糖尿病伤口愈合。
内皮细胞的铁死亡导致糖尿病伤口血管化受损。ApoVs代表了一种有前景的无细胞治疗方法，可减轻铁死亡、恢复内皮功能并促进血管生成，为糖尿病伤口管理提供了一种潜在策略。
