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IF 3.1 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Acta Diabetologica Pub Date : 2024-12-16 DOI:10.1007/s00592-024-02422-x

Yinji Luo, Qijie Guo, Chang Liu, Yuxuan Zheng, Yichong Wang, Bin Wang

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引用次数: 0

摘要

目的：糖尿病足溃疡（DFU）会导致严重的发病率和死亡率。脂肪间充质干细胞（ASC）衍生的细胞外囊泡（EVs）具有促进糖尿病伤口愈合的特性，我们探讨了它们在糖尿病足溃疡大鼠中的作用：方法：体外培养 ASCs，进行传代，然后通过流式细胞术和诱导成骨/成脂分化进行鉴定。提取并鉴定 ASC-EV。用ASC-EVs治疗DFU大鼠模型。在体外用 ASC-EVs 或 3-MA 和 sh-PINK1 质粒处理高糖（HG）诱导的大鼠真皮成纤维细胞。观察伤口愈合情况。组织学变化、炎症细胞因子（TNF-α、IL-1β）、α-SMA 和 p21 双阳性细胞水平均通过 HE 染色、ELISA 和免疫荧光进行了评估。通过荧光染料JC-1、CCK-8、SA-β-gal染色和ROS试剂盒评估线粒体膜电位（MMP）、细胞活力和衰老以及细胞中ROS的产生：结果：DFU大鼠伤口愈合缓慢，IL-1β、TNF-α、α-SMA和p21双阳性细胞及SA-β-gal水平升高，而HG诱导的细胞活力减弱，ROS、SA-β-gal、p21和p62蛋白水平升高，LC3II/I、PINK1和parkin蛋白水平及MMP下降，ASC-EVs可逆转这些现象。HG通过抑制PINK1/parkin通路来抑制有丝分裂，从而加速真皮成纤维细胞的衰老。PINK1/parkin通路的抑制在一定程度上减轻了ASC-EVs的作用。ASC-EVs在体内通过激活PINK1/parkin通路促进有丝分裂：结论：ASC-EVs通过激活PINK1/parkin通路介导有丝分裂，从而阻碍HG诱导的大鼠真皮成纤维细胞衰老并促进DFU大鼠的伤口愈合。

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Adipose mesenchymal stem cell-derived extracellular vesicles regulate PINK1/parkin-mediated mitophagy to repair high glucose-induced dermal fibroblast senescence and promote wound healing in rats with diabetic foot ulcer.

Aims: Diabetic foot ulcers (DFUs) cause prominent morbidity and mortality. Adipose mesenchymal stem cell (ASC)-derived extracellular vesicles (EVs) show property in facilitating diabetic wound healing, and we explored their role in DFU rats.

Methods: ASCs were cultured in vitro, passaged and then identified by flow cytometry and induction of osteogenic/adipogenic differentiation. ASC-EVs were extracted and identified. DFU rat model was treated with ASC-EVs. High glucose (HG)-induced rat dermal fibroblasts were treated with ASC-EVs or 3-MA and sh-PINK1 plasmid in vitro. Wound healing was observed. Histological changes, inflammatory cytokines (TNF-α, IL-1β), and α-SMA and p21 double-positive cell level were assessed by HE staining, ELISA, and immunofluorescence. Mitochondrial membrane potential (MMP), cell viability and senescence, and ROS production in cells were assessed by fluorescence dye JC-1, CCK-8, SA-β-gal staining, and ROS kit. p21, LC3II/I, p62, PINK1 and parkin protein levels were determined by Western blot.

Results: DFU rats had slow wound healing and elevated levels of IL-1β, TNF-α, α-SMA and p21 double-positive cells, and SA-β-gal, while HG-induced cells had weakened viability, elevated ROS, SA-β-gal, p21 and p62 protein levels, and decreased LC3II/I, PINK1 and parkin protein levels and MMP, which were reversed by ASC-EVs. HG inhibited mitophagy by suppressing the PINK1/parkin pathway to accelerate dermal fibroblast senescence. The PINK1/parkin pathway inhibition partly mitigated the effect of ASC-EVs. ASC-EVs promoted mitophagy by activating the PINK1/parkin pathway in vivo.

Conclusions: ASC-EVs mediated mitophagy by activating the PINK1/parkin pathway, thereby impeding HG-induced rat dermal fibroblast senescence and promoting wound healing in DFU rats.

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来源期刊

Acta Diabetologica 医学-内分泌学与代谢

CiteScore

7.30

自引率

2.60%

发文量

180

审稿时长

2 months

期刊介绍： Acta Diabetologica is a journal that publishes reports of experimental and clinical research on diabetes mellitus and related metabolic diseases. Original contributions on biochemical, physiological, pathophysiological and clinical aspects of research on diabetes and metabolic diseases are welcome. Reports are published in the form of original articles, short communications and letters to the editor. Invited reviews and editorials are also published. A Methodology forum, which publishes contributions on methodological aspects of diabetes in vivo and in vitro, is also available. The Editor-in-chief will be pleased to consider articles describing new techniques (e.g., new transplantation methods, metabolic models), of innovative importance in the field of diabetes/metabolism. Finally, workshop reports are also welcome in Acta Diabetologica.