Exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-Ex) play important roles in immune and inflammation diseases. However, the role of hUCMSC-Ex in atherosclerosis has not been elucidated. In this study, the isolated exosomes were identified by transmission electron microscopy and nanoparticle tracking analysis. Exosome marker protein levels were increased in the hUCMSC-Ex compared with those in hUCMSC suspension, indicating that exosomes were successfully isolated from hUCMSCs. Furthermore, eosinophils were treated with oxidized low-density lipoprotein (ox-LDL) to construct inflammation model and then incubated with hUCMSC-Ex derived from hUCMSCs which were transfected with miR-100-5p mimic or miR-100-5p inhibitor. We found that hUCMSC-Ex increased miR-100-5p expression, inhibited cell migration, promoted cell apoptosis, and reduced inflammatory cytokine levels in ox-LDL-treated eosinophils, and miR-100-5p overexpression in hUCMSCs enhanced these effects, while miR-100-5p inhibition reversed these effects. Moreover, frizzled 5 (FZD5) was a target gene of miR-100-5p. FZD5 overexpression reversed the inhibitory effects of hUCMSC-Ex-miR-100-5p on cell progression and inflammation in eosinophils. Additionally, hUCMSC-Ex-miR-100-5p decreased the expression of cyclin D1 and β-catenin proteins. Wnt/β-catenin pathway activator BML-284 effectively reversed the effects of hUCMSC-Ex-miR-100-5p on cell progression and inflammation in eosinophils. ApoE^−/− mice were fed with high-fat diet to construct an atherosclerosis mice model, and hUCMSC-Ex was injected into mice. hUCMSC-Ex reduced atherosclerotic plaque area and inflammation response in atherosclerosis mice. This study demonstrates that hUCMSC-Ex-miR-100-5p inhibits cell progression and inflammatory response in eosinophils via the FZD5/Wnt/β-catenin pathway, thereby alleviating atherosclerosis progression.

中文翻译：

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人脐带间充质干细胞衍生外泌体中的 miR-100-5p 通过 FZD5/Wnt/β-catenin 通路介导嗜酸性粒细胞炎症减轻动脉粥样硬化

源自人脐带间充质干细胞 (hUCMSC-Ex) 的外泌体在免疫和炎症疾病中发挥重要作用。然而，尚未阐明 hUCMSC-Ex 在动脉粥样硬化中的作用。在这项研究中，分离的外泌体通过透射电子显微镜和纳米粒子追踪分析进行了鉴定。与 hUCMSC 悬浮液相比，hUCMSC-Ex 中的外泌体标记蛋白水平增加，表明外泌体已成功从 hUCMSCs 中分离出来。此外，用氧化低密度脂蛋白（ox-LDL）处理嗜酸性粒细胞以构建炎症模型，然后与转染miR-100-5p模拟物或miR-100-5p抑制剂的hUCMSCs衍生的hUCMSC-Ex孵育。我们发现 hUCMSC-Ex 增加 miR-100-5p 表达，抑制细胞迁移，促进细胞凋亡，并且降低了 ox-LDL 处理的嗜酸性粒细胞中的炎性细胞因子水平，并且 miR-100-5p 在 hUCMSCs 中过表达增强了这些作用，而 miR-100-5p 抑制逆转了这些作用。而且，frizzled 5 ( FZD5 ) 是 miR-100-5p 的靶基因。FZD5 过表达逆转了 hUCMSC-Ex-miR-100-5p 对嗜酸性粒细胞进展和炎症的抑制作用。此外，hUCMSC-Ex-miR-100-5p 降低了 cyclin D1 和 β-catenin 蛋白的表达。Wnt/β-catenin 通路激活剂 BML-284 有效逆转 hUCMSC-Ex-miR-100-5p 对嗜酸性粒细胞进展和炎症的影响。ApoE ^-/-以高脂饮食喂养小鼠构建动脉粥样硬化小鼠模型，并将hUCMSC-Ex注射入小鼠体内。hUCMSC-Ex 减少了动脉粥样硬化小鼠的动脉粥样硬化斑块面积和炎症反应。本研究表明，hUCMSC-Ex-miR-100-5p 通过 FZD5/Wnt/β-catenin 通路抑制嗜酸性粒细胞的细胞进展和炎症反应，从而缓解动脉粥样硬化的进展。