Extracellular vesicles from adipose-derived stem cells promote microglia M2 polarization and neurological recovery in a mouse model of transient middle cerebral artery occlusion

Xiaowen Hu; Jiaji Pan; Yongfang Li; Yixu Jiang; Haoran Zheng; Rubing Shi; Qi Zhang; Chang Liu; Hengli Tian; Zhijun Zhang; Yaohui Tang; Guo-Yuan Yang; Yongting Wang

doi:10.1186/s13287-021-02668-0

Extracellular vesicles from adipose-derived stem cells promote microglia M2 polarization and neurological recovery in a mouse model of transient middle cerebral artery occlusion

Stem Cell Res Ther. 2022 Jan 20;13(1):21. doi: 10.1186/s13287-021-02668-0.

Authors

Xiaowen Hu¹, Jiaji Pan¹, Yongfang Li², Yixu Jiang¹, Haoran Zheng¹, Rubing Shi¹, Qi Zhang¹, Chang Liu¹, Hengli Tian¹, Zhijun Zhang¹, Yaohui Tang¹, Guo-Yuan Yang^{3

4}, Yongting Wang⁵

Affiliations

¹ Shanghai Sixth People's Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
² Department of Rehabilitation and Institute of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
³ Shanghai Sixth People's Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. gyyang@sjtu.edu.cn.
⁴ Department of Rehabilitation and Institute of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China. gyyang@sjtu.edu.cn.
⁵ Shanghai Sixth People's Hospital and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China. ytwang@sjtu.edu.cn.

Abstract

Background: Adipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood. The current study aimed to explore the contribution of miRNAs in ADSC-EVs to the treatment of cerebral ischemia.

Methods: After the intravenous injection of ADSC-EVs, therapeutic efficacy was evaluated by neurobehavioral tests and brain atrophy volume. The polarization of microglia was assessed by immunostaining and qPCR. We further performed miRNA sequencing of ADSC-EVs and analyzed the relationship between the upregulated miRNAs in ADSC-EVs and microglial polarization-related proteins using Ingenuity Pathway Analysis (IPA).

Results: The results showed that ADSC-EVs reduced brain atrophy volume, improved neuromotor and cognitive functions after mouse ischemic stroke. The loss of oligodendrocytes was attenuated after ADSC-EVs injection. The number of blood vessels, as well as newly proliferated endothelial cells in the peri-ischemia area were higher in the ADSC-EVs treated group than that in the PBS group. In addition, ADSC-EVs regulated the polarization of microglia, resulting in increased repair-promoting M2 phenotype and decreased pro-inflammatory M1 phenotype. Finally, STAT1 and PTEN were highlighted as two downstream targets of up-regulated miRNAs in ADSC-EVs among 85 microglia/macrophage polarization related proteins by IPA. The inhibition of STAT1 and PTEN by ADSC-EVs were confirmed in cultured microglia.

Conclusions: In summary, ADSC-EVs reduced ischemic brain injury, which was associated with the regulation of microglial polarization. miRNAs in ADSC-EVs partly contributed to their function in regulating microglial polarization by targeting PTEN and STAT1.

Keywords: Adipose-derived stem cell; Cerebral ischemia; Extracellular vesicles; Microglial polarization; miRNAs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Ischemia* / metabolism
Cells, Cultured
Endothelial Cells / metabolism
Extracellular Vesicles* / metabolism
Infarction, Middle Cerebral Artery / therapy
Mice
Microglia / metabolism
Stem Cells / metabolism