Department of Vascular Surgery, The Quzhou Affliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, No. 100 Minjiang Avenue, Quzhou 324000, China.
Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Pujian Road 160, Shanghai 200127, China.
Int J Biol Sci. 2024 Jun 17;20(9):3515-3529. doi: 10.7150/ijbs.97150. eCollection 2024.
Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. and experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.
血管生成受损是糖尿病伤口愈合延迟的主要因素。功能失调的线粒体促进中性粒细胞胞外诱捕网（NETs）的形成，在伤口愈合过程中阻碍血管生成。间充质干细胞衍生的细胞外囊泡（MSC-EVs）在促进糖尿病组织修复和再生方面显示出前景；然而，这一过程中涉及的确切途径仍不清楚。在这项研究中，评估了糖尿病患者和动物模型的伤口样本中 NET 诱导的内皮细胞（ECs）铁死亡和血管生成。并进行了 实验，使用特定抑制剂和基因敲除小鼠研究 NET 在 ECs 中的调节机制。封装功能失调线粒体的 MSC-EVs 被用于触发中性粒细胞中的线粒体融合并恢复线粒体功能，以抑制 NET 的形成。使用彩色激光多普勒成像和血管密度分析评估伤口组织中的血管生成。通过宏观分析和上皮间隙的组织学评估评估伤口愈合。验证了 NET 诱导的 ECs 铁死亡是导致糖尿病伤口血管生成受损的关键因素。从机制上讲，NET 通过抑制 PI3K/AKT 途径来调节铁死亡。此外，MSC-EVs 将功能性线粒体转移到伤口组织中的中性粒细胞中，触发线粒体融合并恢复线粒体功能，从而减少 NET 的形成。这些结果表明，抑制 NET 形成和 EC 铁死亡或激活 PI3K/AKT 途径可以显著改善伤口愈合。总之，这项研究揭示了糖尿病伤口愈合中涉及的一种新的 NET 介导途径，并提出了一种加速伤口愈合的有效治疗策略。
