C-C Chemokine Receptor Type 2-overexpressing Exosomes Alleviated Experimental Post-stroke Cognitive Impairment by Enhancing Microglia/macrophage M2 Polarization

Overview

Journal World J Stem Cells

Publisher Baishideng Publishing Group

Date 2020 Mar 19

PMID 32184939

Citations 28

Authors

Huai-Chun Yang

Min Zhang

Rui Wu

Hai-Qing Zheng

Li-Ying Zhang

Jing Luo

Li-Li Li

Xi-Quan Hu

Affiliations

Soon will be listed here.

Abstract

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) 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.

Aim: To investigate the effects of Exo on PSCI and whether Exo can enhance therapeutic effects on PSCI.

Methods: 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.

Results: 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.

Conclusion: 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.

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References

Thomi G, Surbek D, Haesler V, Joerger-Messerli M, Schoeberlein A . Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury. Stem Cell Res Ther. 2019; 10(1):105. PMC: 6429800. DOI: 10.1186/s13287-019-1207-z. View

Phinney D, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix C . Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015; 6:8472. PMC: 4598952. DOI: 10.1038/ncomms9472. View

Deramecourt V, Pasquier F . Neuronal substrate of cognitive impairment in post-stroke dementia. Brain. 2014; 137(Pt 9):2404-5. DOI: 10.1093/brain/awu188. View

Ciullo A, Biemmi V, Milano G, Bolis S, Cervio E, Fertig E . Exosomal Expression of CXCR4 Targets Cardioprotective Vesicles to Myocardial Infarction and Improves Outcome after Systemic Administration. Int J Mol Sci. 2019; 20(3). PMC: 6386845. DOI: 10.3390/ijms20030468. View

Lan X, Han X, Li Q, Yang Q, Wang J . Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol. 2017; 13(7):420-433. PMC: 5575938. DOI: 10.1038/nrneurol.2017.69. View

Han L, Cai W, Mao L, Liu J, Li P, Leak R . Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia. Stroke. 2015; 46(9):2628-36. PMC: 4615602. DOI: 10.1161/STROKEAHA.115.010091. View

Dimitrijevic O, Stamatovic S, Keep R, Andjelkovic A . Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke. 2007; 38(4):1345-53. DOI: 10.1161/01.STR.0000259709.16654.8f. View

Bejot Y, Giroud M . Mean age at stroke onset: an instructive tool from epidemiological studies. Eur J Neurol. 2008; 16(1):e3. DOI: 10.1111/j.1468-1331.2008.02360.x. View

Zhao Y, Gibb S, Zhao J, Moore A, Hylin M, Menge T . Wnt3a, a Protein Secreted by Mesenchymal Stem Cells Is Neuroprotective and Promotes Neurocognitive Recovery Following Traumatic Brain Injury. Stem Cells. 2016; 34(5):1263-72. DOI: 10.1002/stem.2310. View

10.

Xin H, Li Y, Cui Y, Yang J, Zhang Z, Chopp M . Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013; 33(11):1711-5. PMC: 3824189. DOI: 10.1038/jcbfm.2013.152. View

11.

Miron V, Franklin R . Macrophages and CNS remyelination. J Neurochem. 2014; 130(2):165-71. DOI: 10.1111/jnc.12705. View

12.

Ding M, Shen Y, Wang P, Xie Z, Xu S, Zhu Z . Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer's Disease. Neurochem Res. 2018; 43(11):2165-2177. DOI: 10.1007/s11064-018-2641-5. View

13.

Farzamfar S, Hasanpour A, Nazeri N, Razavi H, Salehi M, Shafei S . Extracellular micro/nanovesicles rescue kidney from ischemia-reperfusion injury. J Cell Physiol. 2019; 234(8):12290-12300. DOI: 10.1002/jcp.27998. View

14.

Zhang Y, Hao Z, Wang P, Xia Y, Wu J, Xia D . Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell Prolif. 2019; 52(2):e12570. PMC: 6496165. DOI: 10.1111/cpr.12570. View

15.

Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos M, Rodriguez-Frutos B, Pascual-Guerra J, Fuentes B . White Matter Repair After Extracellular Vesicles Administration in an Experimental Animal Model of Subcortical Stroke. Sci Rep. 2017; 7:44433. PMC: 5353554. DOI: 10.1038/srep44433. View

16.

Barry F, Murphy J, English K, Mahon B . Immunogenicity of adult mesenchymal stem cells: lessons from the fetal allograft. Stem Cells Dev. 2005; 14(3):252-65. DOI: 10.1089/scd.2005.14.252. View

17.

Moisan A, Favre I, Rome C, De Fraipont F, Grillon E, Coquery N . Intravenous Injection of Clinical Grade Human MSCs After Experimental Stroke: Functional Benefit and Microvascular Effect. Cell Transplant. 2016; 25(12):2157-2171. DOI: 10.3727/096368916X691132. View

18.

Yu B, Shao H, Su C, Jiang Y, Chen X, Bai L . Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 2016; 6:34562. PMC: 5043341. DOI: 10.1038/srep34562. View

19.

Huang Y, Wang J, Cai J, Qiu Y, Zheng H, Lai X . Targeted homing of CCR2-overexpressing mesenchymal stromal cells to ischemic brain enhances post-stroke recovery partially through PRDX4-mediated blood-brain barrier preservation. Theranostics. 2019; 8(21):5929-5944. PMC: 6299433. DOI: 10.7150/thno.28029. View

20.

Hughes P, Allegrini P, Rudin M, Perry V, Mir A, Wiessner C . Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab. 2002; 22(3):308-17. DOI: 10.1097/00004647-200203000-00008. View