C-C chemokine receptor type 2-overexpressing exosomes alleviated experimental post-stroke cognitive impairment by enhancing microglia/macrophage M2 polarization

• 作者: Hai-Qing Zheng Huai-Chun Yang Jing Luo Li-Li Li Li-Ying Zhang Min Zhang Rui Wu Xi-Quan Hu
• 来源期刊: 世界干细胞杂志:英文版(电子版)
• 学科: 医学
• 关键词: Cognitive impairment Stroke EXOSOMES C-C chemokine receptor TYPE 2 Microglia/macrophage POLARIZATION Remyelination
• 年，卷（期）: 2020,（2）
• 页码范围: 152-167
• 页数: 16页
• 分类号: R73

摘要

BACKGROUND Human-derived mesenchymal stromal cells have been shown to improve cognitive function following experimental stroke. The activity of exosomes has been verified to be comparable to the therapeutic effects of mesenchymal stromal cells. However, the effects of exosomes derived from human umbilical cord mesenchymal stem cells(HUC-MSCs)(Exo Ctrl) on post-stroke cognitive impairment(PSCI) have rarely been reported. Moreover, whether exosomes derived from C-C chemokine receptor type 2(CCR2)-overexpressing HUC-MSCs(ExoCCR2) can enhance the therapeutic effects on PSCI and the possible underlying mechanisms have not been studied.AIM To investigate the effects of Exo Ctrl on PSCI and whether ExoCCR2 can enhance therapeutic effects on PSCI.METHODS Transmission electron microscopy, q Nano? particles analyzer, and Western blotting were employed to determine the morphology and CCR2 expression of Exo Ctrl or ExoCCR2. ELISA was used to study the binding capacity of exosomes to CC chemokine ligand 2(CCL2) in vivo. After the intravenous injection of Exo Ctrl or ExoCCR2 into experimental rats, the effect of Exo Ctrl and ExoCCR2 on PSCI was assessed by Morris water maze. Remyelination and oligodendrogenesis were analyzed by Western blotting and immunofluorescence microscopy. QRT-PCR and immunofluorescence microscopy were conducted to compare the microglia/macrophage polarization. The infiltration and activation of hematogenous macrophages were analyzed by Western blotting and transwellmigration analysis.RESULTS CCR2-overexpressing HUC-MSCs loaded the CCR2 receptor into their exosomes.The morphology and diameter distribution between Exo Ctrl and ExoCCR2 showed no significant difference. ExoCCR2 bound significantly to CCL2 but Exo Ctrl showed little CCL2 binding. Although both ExoCCR2 and Exo Ctrl showed beneficial effects on PSCI, oligodendrogenesis, remyelination, and microglia/macrophage polarization, ExoCCR2 exhibited a significantly superior beneficial effect. We also found that ExoCCR2 could suppress the CCL2-induced m