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工程化富含miR-214的雪旺细胞衍生细胞外囊泡增强了对2型糖尿病小鼠周围神经病变的治疗效果。

Engineered miR-214 enriched Schwann cell-derived extracellular vesicles amplify therapeutic efficacy for peripheral neuropathy in T2D mice.

作者信息

Wang Lei, Lu Xuerong, Szalad Alexandra, Zhang Yi, Li Yanfeng, Lu Mei, Kemper Amy, Liu Zhongwu, Liu Xian Shuang, Chopp Michael, Zhang Zheng Gang

机构信息

Department of Neurology, Henry Ford Health, Detroit, MI, United States.

Department of Biostatistics and Research Epidemiology, Henry Ford Health, Detroit, MI, United States.

出版信息

Front Cell Neurosci. 2025 Aug 29;19:1649830. doi: 10.3389/fncel.2025.1649830. eCollection 2025.

DOI:10.3389/fncel.2025.1649830
PMID:40950414
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12426067/
Abstract

Extracellular vesicles (EVs) derived from healthy Schwann cells (SC-EVs) ameliorate peripheral neuropathy in diabetic mice and rescue sciatic nerve function in Schwann cell Dicer knockout mice in part via SC-EV cargo miRNAs. Among these miRNAs, miR-214 repairs nerve damage. The present study investigated whether engineered SC-EVs with elevated miR-214 (214-EVs), further amplify the therapeutic effect of naïve SC-EVs (naïve-EVs) on reducing diabetic peripheral neuropathy (DPN) in a mouse model of high-fat diet (HFD)-streptozotocin (STZ) induced type 2 diabetes. Compared to naïve-EVs, 214-EVs significantly improved motor and sensory nerve conduction velocity of the sciatic nerve and thermal latency, which were associated with increased intraepidermal nerve fiber density, axonal diameter, and myelin thickness in the sciatic nerve. Quantitative RT-PCR and Western blot analyses of sciatic nerve tissues showed that, compared to naïve-EVs, 214-EVs significantly increased miR-214 levels and downregulated axonal inhibitory protein PTEN and the myelination inhibitory protein cJUN. Furthermore, 214-EVs markedly suppressed neuroinflammation by decreasing CD68 + macrophages and inactivating the TLR4/NF-κB signaling pathway. Collectively, our findings demonstrate that miR-214-enriched SC-EVs are superior to naïve-EVs to ameliorate DPN and represent a promising EV-based therapeutic strategy.

摘要

源自健康雪旺细胞的细胞外囊泡（SC-EVs）可改善糖尿病小鼠的周围神经病变，并部分通过SC-EV携带的微小RNA（miRNAs）挽救雪旺细胞Dicer基因敲除小鼠的坐骨神经功能。在这些miRNA中，miR-214可修复神经损伤。本研究调查了miR-214含量升高的工程化雪旺细胞外囊泡（214-EVs）是否能进一步增强天然雪旺细胞外囊泡（天然-EVs）对高脂饮食（HFD）-链脲佐菌素（STZ）诱导的2型糖尿病小鼠模型中糖尿病周围神经病变（DPN）的治疗效果。与天然-EVs相比，214-EVs显著改善了坐骨神经的运动和感觉神经传导速度以及热潜伏期，这与坐骨神经中表皮内神经纤维密度、轴突直径和髓鞘厚度增加有关。对坐骨神经组织进行定量逆转录聚合酶链反应（RT-PCR）和蛋白质免疫印迹分析表明，与天然-EVs相比，214-EVs显著提高了miR-214水平，并下调了轴突抑制蛋白PTEN和髓鞘形成抑制蛋白cJUN。此外，214-EVs通过减少CD68 +巨噬细胞和使Toll样受体4（TLR4）/核因子κB（NF-κB）信号通路失活，显著抑制了神经炎症。总体而言，我们的研究结果表明，富含miR-214的雪旺细胞外囊泡在改善DPN方面优于天然-EVs，代表了一种基于细胞外囊泡的有前景的治疗策略。

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本文引用的文献

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Signal Transduct Target Ther. 2025 Apr 25;10(1):132. doi: 10.1038/s41392-025-02175-1.
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Clinical value of serum miR-214-3p expression in the diagnosis of type 2 diabetes mellitus and prediction of its chronic complications.血清miR-214-3p表达在2型糖尿病诊断及慢性并发症预测中的临床价值
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Downregulation of miR-214 promotes dilated Cardiomyopathy Progression through PDE5A-Mediated cGMP regulation.miR-214 的下调通过 PDE5A 介导的 cGMP 调节促进扩张型心肌病的进展。
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Schwann cell-derived exosomes ameliorate peripheral neuropathy induced by ablation of dicer in Schwann cells.雪旺细胞衍生的外泌体可改善由雪旺细胞中Dicer缺失引起的周围神经病变。
Front Cell Neurosci. 2024 Sep 2;18:1462228. doi: 10.3389/fncel.2024.1462228. eCollection 2024.
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Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery.源自脑内皮细胞且微小RNA 27a水平升高的细胞外小囊泡可促进缺血性中风的恢复。
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Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches.细胞外囊泡研究的最低信息要求（MISEV2023）：从基础到先进方法。
J Extracell Vesicles. 2024 Feb;13(2):e12404. doi: 10.1002/jev2.12404.
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