Department of Neurology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, China.
Department of General Surgery, Shanghai Pudong Hospital, Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, China.
Neurosci Lett. 2022 Jan 19;769:136389. doi: 10.1016/j.neulet.2021.136389. Epub 2021 Dec 8.
Previous investigations have shown that exosome secretion from hypoxic pre-treated adipose-derived stem cells (ADSCs) affect ischemic injury treatment; however, the therapeutic effect relative to circRNA delivery is unclear.
In the present investigation inflammatory factors, nerve injury, and cognitive function were assessed using a middle cerebral artery occlusion mouse model. The isolated exosomes were identified using transmission electron microscopy and further tested by leveraging exosome particles in a nanoparticle tracking approach. Differences in circRNA expression between exosomes and hypoxic pre-treated ADSC exosomes were analyzed by high-throughput sequencing. The phenotypic transformation of microglia was detected by immunofluorescence. The circRNA and downstream target were analyzed by bioinformatics, RT-qPCR, and luciferase report.
Exosomes from hypoxic pre-treated ADSCs improved cognitive function by reducing neuronal damage in the hippocampus after cerebral infarction. Exosomes from hypoxic pre-treated ADSCs improved cognitive function via delivery of circ-Rps5. SIRT7 and miR-124-3p were circ-Rps5 downstream targets, which was confirmed by luciferase report analysis. miR-124-3p overexpression or SIRT7 downregulation reversed the circ-Rps5-mediated M2 microglial shift under LPS conditions. Circ-Rps5-modified ADSC exosome improved cognitive function by decreasing neuronal damage and shifting microglia from an M1 to M2 phenotype in the hippocampus.
The study showed that exosomes from hypoxic pre-treated ADSCs attenuated acute ischemic stroke-induced brain injury via delivery of circ-Rps5 and promoted M2 microglia/macrophage polarization.
先前的研究表明，缺氧预处理脂肪间充质干细胞（ADSCs）分泌的外泌体影响缺血性损伤治疗；然而，其相对于 circRNA 传递的治疗效果尚不清楚。
在本研究中，通过大脑中动脉闭塞小鼠模型评估炎症因子、神经损伤和认知功能。使用透射电子显微镜鉴定分离的外泌体，并通过纳米颗粒跟踪方法进一步测试外泌体颗粒。通过高通量测序分析外泌体和缺氧预处理 ADSC 外泌体之间 circRNA 表达的差异。通过免疫荧光检测小胶质细胞的表型转化。通过生物信息学、RT-qPCR 和荧光素酶报告分析 circRNA 和下游靶标。
缺氧预处理 ADSC 来源的外泌体通过减少脑梗死海马区神经元损伤改善认知功能。缺氧预处理 ADSC 来源的外泌体通过递送 circ-Rps5 改善认知功能。SIRT7 和 miR-124-3p 是 circ-Rps5 的下游靶标，这通过荧光素酶报告分析得到证实。miR-124-3p 过表达或 SIRT7 下调逆转了 LPS 条件下 circ-Rps5 介导的 M2 小胶质细胞转移。circ-Rps5 修饰的 ADSC 外泌体通过减少神经元损伤和将小胶质细胞从 M1 表型转变为 M2 表型来改善认知功能。
该研究表明，缺氧预处理 ADSC 来源的外泌体通过递送 circ-Rps5 减轻急性缺血性脑卒中引起的脑损伤，并促进 M2 小胶质细胞/巨噬细胞极化。
