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Exosomes derived from microRNA-138-5p-overexpressing bone marrow-derived mesenchymal stem cells confer neuroprotection to astrocytes following ischemic stroke via inhibition of LCN2.
Journal of Biological Engineering ( IF 5.7 ) Pub Date : 2019-08-28 , DOI: 10.1186/s13036-019-0193-0
Yiming Deng 1, 2, 3 , Duanduan Chen 4 , Feng Gao 1, 2, 3 , Hong Lv 5 , Guojun Zhang 5 , Xuan Sun 1, 2, 3 , Lian Liu 1, 2, 3 , Dapeng Mo 1, 2, 3 , Ning Ma 1, 2, 3 , Ligang Song 1, 2, 3 , Xiaochuan Huo 1, 2, 3 , Tianyi Yan 4 , Jingbo Zhang 1, 2, 3 , Zhongrong Miao 1, 2, 3
Affiliation  

Background MicroRNAs (miRNAs) are implicated in the progression of ischemic stroke (IS) and bone marrow-derived mesenchymal stem cells (BMSCs)-derived exosomes play a role in IS therapy. Herein we hypothesized that the BMSCs-derived exosomes containing overexpressed miR-138-5p could protect the astrocytes following IS involved with lipocalin 2 (LCN2). Methods The differentially expressed gene related to IS was initially identified by bioinformatics analysis. miR-138-5p was predicted to regulate LCN2. The expression of miR-138-5p and LCN2 was altered in the oxygen-glucose deprivation (OGD)-induced astrocytes. Furthermore, the cell behaviors and inflammatory responses were evaluated both in astrocytes alone and astrocytes co-cultured with exosomes derived from BMSCs overexpressing miR-138-5p to explore the involvement of miR-138-5p and LCN2 in IS. Besides, middle cerebral artery occlusion (MCAO) mouse model was established to explore the effect of BMSCs-derived exosomal miR-138-5p in IS in vivo. Results LCN2 was highly expressed in IS. Besides, LCN2 was a target gene of miR-138-5p. BMSCs-derived exosomes could be endocytosed by astrocytes via co-culture. Overexpression of miR-138-5p promoted the proliferation and inhibited apoptosis of astrocytes injured by OGD, accompanied by the reduced expression of inflammatory factors, which was achieved by down-regulating LCN2. More importantly, BMSCs delivered miR-138-5p to the astrocytes via exosomes and BMSCs-derived exosomal miR-138-5p alleviated neuron injury in IS mice. Conclusion BMSCs-derived exosomal miR-138-5p reduces neurological impairment by promoting proliferation and inhibiting inflammatory responses of astrocytes following IS by targeting LCN2, which may provide a novel target for IS treatment.

中文翻译:

源自过表达 microRNA-138-5p 的骨髓间充质干细胞的外泌体通过抑制 LCN2 对缺血性中风后的星形胶质细胞提供神经保护。

背景 MicroRNAs (miRNAs) 与缺血性卒中 (IS) 的进展有关,而骨髓来源的间充质干细胞 (BMSCs) 来源的外泌体在 IS 治疗中发挥作用。在这里,我们假设含有过表达 miR-138-5p 的 BMSCs 衍生的外泌体可以保护与脂质运载蛋白 2 (LCN2) 相关的 IS 后的星形胶质细胞。方法通过生物信息学分析初步鉴定出与IS相关的差异表达基因。预测 miR-138-5p 调节 LCN2。miR-138-5p 和 LCN2 的表达在氧葡萄糖剥夺 (OGD) 诱导的星形胶质细胞中发生了改变。此外,在单独的星形胶质细胞和与来自过度表达 miR-138-5p 的 BMSCs 的外泌体共培养的星形胶质细胞中评估细胞行为和炎症反应,以探索 miR-138-5p 和 LCN2 在 IS 中的参与。此外,建立大脑中动脉闭塞(MCAO)小鼠模型,探讨BMSCs衍生的外泌体miR-138-5p在体内IS的作用。结果 LCN2在IS中高表达。此外,LCN2是miR-138-5p的靶基因。BMSCs 衍生的外泌体可以通过共培养被星形胶质细胞内吞。miR-138-5p的过表达促进OGD损伤的星形胶质细胞增殖并抑制其凋亡,同时降低炎症因子的表达,这是通过下调LCN2来实现的。更重要的是,BMSCs 通过外泌体将 miR-138-5p 递送至星形胶质细胞,BMSCs 衍生的外泌体 miR-138-5p 减轻了 IS 小鼠的神经元损伤。
更新日期:2020-04-22
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