Background Ferroptosis plays an essential role in the development of diabetes and its complications, suggesting its potential as a therapeutic target. Stem cell-derived extracellular vesicles (EVs) are increasingly being developed as nano-scale drug carriers. The aim of this study was to determine the role of ferroptosis in the pathogenesis of diabetic wound healing and evaluate the therapeutic effects of coenzyme Q10 (Q10)-stimulated exosmes derived from mesenchymal stem cells (MSCs). Methods Human keratinocytes (HaCaTs) were exposed to high glucose (HG) conditions in vitro to mimic diabetic conditions, and the ferroptosis markers and expression level of acyl-coenzyme A synthase long-chain family member 4 (ACSL4) were determined. Exosomes were isolated from control and Q10-primed umbilical cord mesenchymal stem cells (huMSCs) and characterized by tramsmission electron microscopy and immunofluorescence staining. The HG-treated HaCaTs were cultured in the presence of exosomes derived from Q10-treated huMSCs (Q10-Exo) and their in vitro migratory capacity was analyzed. Results Q10-Exo significantly improved keratinocyte viability and inhibited ferroptosis in vitro. miR-548ai and miR-660 were upregulated in the Q10-Exo and taken up by HaCaT cells. Furthermore, miR-548ai and miR-660 mimics downregulated ACSL4-inhibited ferroptosis in the HG-treated HaCaT cells and enhanced their proliferation and migration. However, simultaneous upregulation of ACSL4 reversed their effects. Q10-Exo also accelerated diabetic wound healing in a mouse model by inhibiting ACSL4-induced ferroptosis. Conclusions Q10-Exo promoted the proliferation and migration of keratinocytes and inhibited ferroptosis under hyperglycemic conditions by delivering miR-548ai and miR-660. Q10-Exo also enhanced cutaneous wound healing in diabetic mice by repressing ACSL4-mediated ferroptosis.

中文翻译：

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Q10 工程间充质干细胞衍生外泌体在抑制糖尿病伤口愈合铁死亡中的作用


背景 铁死亡在糖尿病及其并发症的发展中起着至关重要的作用，表明其作为治疗靶点的潜力。干细胞衍生的细胞外囊泡 （EV） 越来越多地被开发为纳米级药物载体。本研究的目的是确定铁死亡在糖尿病伤口愈合发病机制中的作用，并评价来源于间充质干细胞 （MSCs） 的辅酶 Q10 （Q10） 刺激的外泌体的治疗效果。方法 将人角质形成细胞 （HaCaTs） 体外暴露于高葡萄糖 （HG） 条件下模拟糖尿病情况，测定铁死亡标志物和酰基辅酶 A 合酶长链家族成员 4 （ACSL4） 的表达水平。从对照和 Q10 引发的脐带间充质干细胞 （huMSCs） 中分离外泌体，并通过 tramsmission 电子显微镜和免疫荧光染色进行表征。HG 处理的 HaCaTs 在来源于 Q10 处理的 huMSC （Q10-Exo） 的外泌体存在下培养，并分析它们的体外迁移能力。结果 Q10-Exo 在体外显著提高角质形成细胞活力并抑制铁死亡。miR-548ai 和 miR-660 在 Q10-Exo 中上调并被 HaCaT 细胞摄取。此外，miR-548ai 和 miR-660 模拟下调 HG 处理的 HaCaT 细胞中 ACSL4 抑制的铁死亡，并增强其增殖和迁移。然而，ACSL4 的同时上调逆转了它们的作用。Q10-Exo 还通过抑制 ACSL4 诱导的铁死亡来加速小鼠模型中糖尿病伤口的愈合。结论 Q10-Exo 通过递送 miR-548ai 和 miR-660 促进高血糖条件下角质形成细胞的增殖和迁移并抑制铁死亡。 Q10-Exo 还通过抑制 ACSL4 介导的铁死亡来增强糖尿病小鼠的皮肤伤口愈合。