Research Paper|Volume 13, Issue 3|pp 4079—4095

Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1

Dianquan Zhang¹, Guoliang Cai^2,³, Kai Liu⁴, Zhe Zhuang⁵, Kunping Jia⁴, Siying Pei⁴, Xiuzhen Wang⁴, Hong Wang⁴, Shengnan Xu⁶, Cheng Cui⁶, Manchao Sun⁶, Sihui Guo⁶, Wenli Song³, Guofeng Cai^4,⁷

¹Department of Rehabilitation Medicine, Shenzhen Longhua District Central Hospital, Shenzhen, China
²Postdoctoral Research Workstation of Harbin Sport University, Harbin 150008, China
³Harbin Sport University, Harbin 150008, China
⁴Hanan Branch of Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
⁵Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150001, China
⁶Heilongjiang University of Traditional Chinese Medicine, Harbin, China
⁷Postdoctoral Research Station of Heilongjiang Academy of Traditional Chinese Medicine, Harbin, China

* Co-first authors

Received: April 21, 2020Accepted: September 28, 2020Published: January 10, 2021

https://doi.org/10.18632/aging.202373

Copyright: © 2021 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo. BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.