Published online Feb 26, 2020. doi: 10.4252/wjsc.v12.i2.152
Peer-review started: October 22, 2019
First decision: November 18, 2019
Revised: December 27, 2019
Accepted: January 19, 2020
Article in press: January 19, 2020
Published online: February 26, 2020
Post-stroke cognitive impairment (PSCI) is a common sequela of stroke with considerable impact on the health well-being and quality of life to patients, and poses significant financial burden on society. Exosomes have been shown to possess therapeutic effects that are comparable to the mesenchymal stromal cells. However, few studies have focused on the effects of exosomes derived from human umbilical cord mesenchymal stem cells (HUC-MSCs) (ExoCtrl) on PSCI. Here in this study, we aimed to explore the if exosomes derived from C-C chemokine receptor type 2 (CCR2)-overexpressing HUC-MSCs (ExoCCR2) have any therapeutic effects on PSCI, and clarify the possible underlying mechanisms.
Effective treatment strategies for PSCI in stroke patients are an unmet clinical need.
In the present study, we aimed to: (1) Investigate whether CCR2 over-expressing exosomes possess improved therapeutic effects on PSCI; and (2) The possible underlying mechanisms involved in the therapeutic benefits of exosomes.
The morphology of ExoCtrl and ExoCCR2 were determined by transmission electron microscopy and qNano® particles analyzer; the CCR2 expression in the ExoCtrl and ExoCCR2 was evaluated by Western blotting; the binding capacity of exosomes to CC chemokine ligand 2 (CCL2) in vivo was examined by ELISA; the effects of ExoCtrl and ExoCCR2 on PSCI in experimental stroke rats were assessed by Morris water maze. Remyelination and oligodendrogenesis was analyzed by Western blotting and immunofluorescence microscopy, and microglia/macrophage polarization were investigated by qRT-PCR and immunofluorescence imaging. The infiltration and activation of hematogenous macrophages were analyzed by transwell migration analysis and Western blotting.
CCR2-overexpressing HUC-MSCs could deliver CCR2 receptor rich exosomes. There were not significant difference in the size and morphology between ExoCtrl and ExoCCR2. ExoCCR2 showed more powerful binding capacity to CCL2, while ExoCtrl hardly bound to CCL2. ExoCCR2 enhanced the beneficial effects of ExoCtrl on PSCI through further promoting microglia/macrophage polarization-mediated oligodendrogenesis and remyelination. Compared with ExoCtrl, ExoCCR2 showed more powerful suppression on CCL2-induced macrophage migration and activation in vivo and in vitro.
CCR2 over-expressing on exosomes showed enhanced therapeutic benefits on PSCI through more powerful modulation on microglia/macrophage polarization-mediated oligo-dendrogenesis and remyelination. The additional therapeutic effect maybe related to the suppression on CCL2-induced macrophage infiltration and activation.
Our study provides great insight in the application of stem cells-based therapies for neural degenerative disorders. Comparisons of the therapeutic effects of ExoCtrl and ExoCCR2 on more clinically relevant animal models of stroke are warranted.