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

• Published in: World journal of stem cells 2020-02, Vol.12 (2), p.152-167
• Main Authors: Yang, Huai-Chun, Zhang, Min, Wu, Rui, Zheng, Hai-Qing, Zhang, Li-Ying, Luo, Jing, Li, Li-Li, Hu, Xi-Quan
• Format: Article
• Language: English
• ISSN: 1948-0210; 1948-0210
• DOI: 10.4252/wjsc.v12.i2.152

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 ) 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 (Exo ) can enhance the therapeutic effects on PSCI and the possible underlying mechanisms have not been studied. To investigate the effects of Exo on PSCI and whether Exo can enhance therapeutic effects on PSCI. Transmission electron microscopy, qNano particles analyzer, and Western blotting were employed to determine the morphology and CCR2 expression of Exo or Exo . ELISA was used to study the binding capacity of exosomes to CC chemokine ligand 2 (CCL2) . After the intravenous injection of Exo or Exo into experimental rats, the effect of Exo and Exo 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 transwell migration analysis. CCR2-overexpressing HUC-MSCs loaded the CCR2 receptor into their exosomes. The morphology and diameter distribution between Exo and Exo showed no significant difference. Exo bound significantly to CCL2 but Exo showed little CCL2 binding. Although both Exo and Exo showed beneficial effects on PSCI, oligodendrogenesis, remyelination, and microglia/macrophage polarization, Exo exhibited a significantly superior beneficial effect. We also found that Exo could suppress the CCL2-induced macrophage migration and activation and , compared with Exo treated group. CCR2 over-expression enhanced the therapeutic effects of exosomes on the experimental PSCI by promoting M2 microglia/macrophage polarization, enhancing oligodendrogenesis and remyelination. These therapeutic effects are likely through suppressing the CCL2-induced hematogenous macrophage migration and activation.