Q10 工程间充质干细胞衍生的外泌体在抑制糖尿病伤口愈合中的铁氧化作用

IF 6.3 1区医学 Q1 DERMATOLOGY

Burns & Trauma Pub Date : 2024-11-27 DOI:10.1093/burnst/tkae054

Ronghua Yang, Sitong Zhou, Jie Huang, Deni Kang, Yao Chen, Xinyi Wang, Yan Shi, Zhengguang Wang

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引用次数: 0

摘要

背景铁蛋白沉积在糖尿病及其并发症的发展过程中起着至关重要的作用，这表明铁蛋白沉积有可能成为治疗靶点。干细胞衍生的细胞外囊泡（EVs）越来越多地被开发为纳米级药物载体。本研究旨在确定铁突变在糖尿病伤口愈合发病机制中的作用，并评估间充质干细胞（MSCs）提取的辅酶Q10（Q10）刺激外泌体的治疗效果。方法在体外将人类角质细胞（HaCaTs）暴露于高糖（HG）条件下以模拟糖尿病条件，并测定铁突变标志物和酰基辅酶A合成酶长链家族成员4（ACSL4）的表达水平。从对照组和 Q10 激发的脐带间充质干细胞（huMSCs）中分离出外泌体，并通过透射电镜和免疫荧光染色对其进行表征。在有 Q10 处理过的 huMSCs 外泌体（Q10-Exo）存在的情况下培养 HG 处理过的 HaCaTs，并分析其体外迁移能力。结果 Q10-Exo 在体外明显提高了角质细胞的活力并抑制了铁凋亡。miR-548ai 和 miR-660 在 Q10-Exo 中上调，并被 HaCaT 细胞吸收。此外，miR-548ai 和 miR-660 模拟物还能下调 HG 处理的 HaCaT 细胞中 ACSL4 抑制的铁凋亡，并增强其增殖和迁移。然而，同时上调 ACSL4 可逆转它们的影响。Q10-Exo 还能通过抑制 ACSL4 诱导的铁蛋白沉积，加速小鼠模型中糖尿病伤口的愈合。结论 Q10-Exo 通过提供 miR-548ai 和 miR-660 促进了角质细胞的增殖和迁移，并抑制了高血糖条件下的铁蛋白沉着。Q10-Exo 还能通过抑制 ACSL4 介导的铁凋亡促进糖尿病小鼠皮肤伤口愈合。

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The role of Q10 engineering mesenchymal stem cell-derived exosomes in inhibiting ferroptosis for diabetic wound healing

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.

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来源期刊

Burns & Trauma 医学-皮肤病学

CiteScore

8.40

自引率

9.40%

发文量

186

审稿时长

6 weeks

期刊介绍： The first open access journal in the field of burns and trauma injury in the Asia-Pacific region, Burns & Trauma publishes the latest developments in basic, clinical and translational research in the field. With a special focus on prevention, clinical treatment and basic research, the journal welcomes submissions in various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, and the prevention and regeneration of burns and trauma injuries. With an expert Editorial Board and a team of dedicated scientific editors, the journal enjoys a large readership and is supported by Southwest Hospital, which covers authors'' article processing charges.