Mesenchymal Stem Cells-Derived Exosomal miR-223-3p Alleviates Ocular Surface Damage and Inflammation by Downregulating Fbxw7 in Dry Eye Models.

IF 5 2区 医学 Q1 OPHTHALMOLOGY
Guifang Wang, Yujie Zhu, Yuzhen Liu, Mulin Yang, Li Zeng
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Abstract

Purpose: Our previous study indicated that exosomes derived from mouse adipose-derived mesenchymal stem cells (mADSC-Exos) alleviated the benzalkonium chloride (BAC)-induced mouse dry eye model. However, the specific active molecules in mADSC-Exos that contribute to anti-dry eye therapy remain unidentified. In this study, we aimed to investigate the efficacy and mechanisms of miR-223-3p derived from mADSC-Exos in dry eye models.

Methods: Enzyme-linked immunosorbent assay (ELISA) experiments were conducted to determine miR-223-3p derived from mADSC-Exos that exerted anti-inflammatory effects on hyperosmolarity-induced mouse corneal epithelial cells (MCECs). The therapeutic efficacy of miR-223-3p was evaluated in mice with dry eye induced by either BAC or scopolamine (Scop). Mice were randomly assigned to 5 groups: sham, model, miR-223-3p overexpression, miR-223-3p knockdown, and 0.1% pranoprofen (positive group). Post-treatment, the severity of dry eye symptoms, and the pro-inflammatory cytokine levels were assessed. The effect of miR-223-3p on silencing the target gene was verified using ELISA and dual luciferase reporter assays.

Results: The mADSC-Exos that knocked out miR-223-3p did not reduce interleukin (IL)-6 content. Supplementing with miR-223-3p could restore the reduction of IL-6. The miR-223-3p effectively ameliorated ocular surface damage and decreased pro-inflammatory cytokines or chemokines in both BAC- and Scop-induced mouse dry eye models. Furthermore, miR-223-3p inhibited cell apoptosis. F-box and WD repeat domain-containing 7 (Fbxw7) was the potential direct target of miR-223-3p. The miR-223-3p suppressed the 3'-untranslated region of Fbxw7. The Fbxw7 knockdown suppressed hyperosmolarity-induced inflammation in MCECs.

Conclusions: The mADSC-derived exosomal miR-223-3p mitigates ocular surface damage and inflammation, indicating its potential as a promising treatment option for dry eye.

间充质干细胞衍生的外泌体 miR-223-3p 在干眼症模型中通过下调 Fbxw7 减轻眼表损伤和炎症。
目的:我们之前的研究表明,从小鼠脂肪间充质干细胞(mADSC-Exos)中提取的外泌体可缓解苯扎氯铵(BAC)诱导的小鼠干眼症模型。然而,mADSC-Exos 中有助于抗干眼症治疗的特定活性分子仍未确定。在这项研究中,我们旨在研究从mADSC-Exos中提取的miR-223-3p在干眼症模型中的疗效和机制:方法:我们进行了酶联免疫吸附试验(ELISA),以确定从mADSC-Exos中提取的miR-223-3p对高渗透性诱导的小鼠角膜上皮细胞(MCECs)具有抗炎作用。在 BAC 或东莨菪碱(Scop)诱导的干眼症小鼠中评估了 miR-223-3p 的疗效。小鼠被随机分为 5 组:假组、模型组、miR-223-3p 过表达组、miR-223-3p 敲除组和 0.1% 普拉洛芬组(阳性组)。治疗后,对干眼症状的严重程度和促炎细胞因子水平进行评估。使用酶联免疫吸附和双荧光素酶报告实验验证了 miR-223-3p 对沉默靶基因的作用:结果:敲除 miR-223-3p 的 mADSC-Exos 没有降低白细胞介素(IL)-6 的含量。补充 miR-223-3p 可以恢复 IL-6 含量的降低。在 BAC 和 Scop 诱导的小鼠干眼症模型中,miR-223-3p 都能有效改善眼表损伤,减少促炎细胞因子或趋化因子。此外,miR-223-3p 还能抑制细胞凋亡。F-box and WD repeat domain-containing 7 (Fbxw7) 是 miR-223-3p 的潜在直接靶标。miR-223-3p 抑制了 Fbxw7 的 3'- 非翻译区。Fbxw7的敲除抑制了高渗透性诱导的MCECs炎症:结论:源自mADSC的外泌体miR-223-3p可减轻眼表损伤和炎症,表明它有望成为干眼症的一种治疗选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.90
自引率
4.50%
发文量
339
审稿时长
1 months
期刊介绍: Investigative Ophthalmology & Visual Science (IOVS), published as ready online, is a peer-reviewed academic journal of the Association for Research in Vision and Ophthalmology (ARVO). IOVS features original research, mostly pertaining to clinical and laboratory ophthalmology and vision research in general.
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