Schwann cell-derived exosomes ameliorate peripheral neuropathy induced by ablation of dicer in Schwann cells

IF 4.2 3区 医学 Q2 NEUROSCIENCES
Lei Wang, XueRong Lu, Alexandra Szalad, Xian Shuang Liu, Yi Zhang, Xinli Wang, William Anthony Golembieski, Brianna Powell, Mikkala Mccann, Mei Lu, Michael Chopp, Zheng Gang Zhang
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引用次数: 0

Abstract

BackgroundMicroRNAs (miRNAs) in Schwann cells (SCs) mediate peripheral nerve function. Ablating Dicer, a key gene in miRNA biogenesis, in SCs causes peripheral neuropathy. Exosomes from healthy SCs (SC-Exo) ameliorate diabetic peripheral neuropathy in part via miRNAs. Thus, using transgenic mice with conditional and inducible ablation of Dicer in proteolipid protein (PLP) expressing SCs (PLP-cKO), we examined whether SC-Exo could reduce peripheral neuropathy in PLP-cKO mice.MethodsPLP-cKO mice at the age of 16 weeks (8 week post-Tamoxifen) were randomly treated with SC-Exo or saline weekly for 8 weeks. Age-and sex-matched wild-type (WT) littermates were used as controls. Peripheral neurological functions, sciatic nerve integrity, and myelination were analyzed. Quantitative RT-PCR and Western blot analyses were performed to examine miRNA and protein expression in sciatic nerve tissues, respectively.ResultsCompared to the WT mice, PLP-cKO mice exhibited a significant decrease in motor and sensory conduction velocities, thermal sensitivity, and motor coordination. PLP-cKO mice exhibited substantial demyelination and axonal damage of the sciatic nerve. Treatment of PLP-cKO mice with SC-Exo significantly ameliorated the peripheral neuropathy and sciatic nerve damage. PLP-cKO mice showed a substantial reduction in a set of Dicer-related miRNAs known to regulate myelination, axonal integrity, and inflammation such as miR-138, −146a and − 338 in the sciatic nerve. In addition, PLP-cKO mice exhibited significant reduction of myelin forming proteins, early growth response 2 (EGR2) and sex determining region Y-box10 (Sox10), but significantly increased myelination inhibitors, Notch1, c-Jun, and Sox2 and the axonal growth inhibitor phosphatase and tens in homolog (PTEN). However, SC-Exo treatment reversed the PLP-cKO altered miRNAs and proteins.ConclusionThis study demonstrates that exogenous SC-Exo ameliorate peripheral neuropathy induced by Dicer ablation in PLP expressing SCs. The therapeutic benefit may be mediated by the SC-Exo altered miRNAs and their targeted genes.
源自许旺细胞的外泌体可改善许旺细胞中 dicer 消融诱发的周围神经病变
背景许旺细胞(SC)中的微RNA(miRNA)介导周围神经功能。消减施旺细胞中 miRNA 生物发生过程中的关键基因 Dicer 会导致周围神经病变。来自健康SC的外泌体(SC-Exo)部分通过miRNA改善糖尿病周围神经病变。因此,我们利用表达蛋白脂质蛋白(PLP)的SC(PLP-cKO)中Dicer的条件性和诱导性消减的转基因小鼠,研究了SC-Exo是否能减轻PLP-cKO小鼠的周围神经病变。年龄和性别匹配的野生型(WT)小鼠作为对照组。对外周神经功能、坐骨神经完整性和髓鞘化进行了分析。结果与 WT 小鼠相比,PLP-cKO 小鼠的运动和感觉传导速度、热敏性和运动协调性显著下降。PLP-cKO 小鼠的坐骨神经表现出严重的脱髓鞘和轴突损伤。用 SC-Exo 治疗 PLP-cKO 小鼠可明显改善周围神经病变和坐骨神经损伤。PLP-cKO小鼠坐骨神经中一组与Dicer相关的miRNA(已知可调控髓鞘化、轴突完整性和炎症)(如miR-138、-146a和-338)大幅减少。此外,PLP-cKO 小鼠表现出髓鞘形成蛋白、早期生长反应 2(EGR2)和性别决定区 Y-box10 (Sox10)的显著减少,但髓鞘形成抑制因子、Notch1、c-Jun 和 Sox2 以及轴突生长抑制因子磷酸酶和同源蛋白(PTEN)的显著增加。然而,SC-Exo 治疗可逆转 PLP-cKO 改变的 miRNA 和蛋白质。这种治疗效果可能是由 SC-Exo 改变的 miRNA 及其靶基因介导的。
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来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
期刊介绍: Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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