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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

Open Access 01-12-2020 | Research

Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization

Authors: Wei Liu, Yuluo Rong, Jiaxing Wang, Zheng Zhou, Xuhui Ge, Chengyue Ji, Dongdong Jiang, Fangyi Gong, Linwei Li, Jian Chen, Shujie Zhao, Fanqi Kong, Changjiang Gu, Jin Fan, Weihua Cai

Published in: Journal of Neuroinflammation | Issue 1/2020

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Abstract

Background

Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism.

Methods

Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms.

Results

Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain- and loss-of-function experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p.

Conclusion

Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.
Appendix
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Metadata
Title
Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization
Authors
Wei Liu
Yuluo Rong
Jiaxing Wang
Zheng Zhou
Xuhui Ge
Chengyue Ji
Dongdong Jiang
Fangyi Gong
Linwei Li
Jian Chen
Shujie Zhao
Fanqi Kong
Changjiang Gu
Jin Fan
Weihua Cai
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-020-1726-7

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