Mechanism of Neural Stem Cell-Derived Exosomal miR-9a-5p Overexpression Improving Survival and Neurogenesis in Ischemic Stroke Rats

Author:

Liu Jiale1,Lin Chaoqun2,Gu Chenyang3,Zhang Qiankun1,Feng Tingle1,Duan Wenjie1,Huang Jiajun1,Long Jun1,Qiu Yunhui4,Ahmed Waqas3,Khan Ahsan Ali5,Cai Hengsen6,Hu Yong7,Zhu Zhihan1,Huang Shiying8,Chen Lukui1

Affiliation:

1. Department of Neurosurgery, Neuroscience Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510310, Guangdong, P.R. China

2. Department of Neurosurgery, University of Chinese Academy of Sciences-Shenzhen Hospital (Guangming District), Shenzhen, 518106, Guangdong, P.R. China

3. Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, P.R. China

4. Department of Pathology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510310, Guangdong, P.R. China

5. Section of Neurosurgery, The Aga Khan University, Karachi, 74800, Sindh, Pakistan

6. Department of Neurosurgery, The Second People’s Hospital of Pingnan, Pingnan, 537300, Guangxi, P.R. China

7. Department of Orthopedics and Traumatology, The University of Hong Kong, Hongkong, 999077, P.R. China

8. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, P.R. China

Abstract

As a momentous condition disease, ischemic stroke could lead to physical disability and death. Here, the protective effect of miRNA up-regulated in neural stem cells (NSCs) derived exosomes on ischemic stroke in rats and their molecular mechanisms were investigated to reveal the therapeutic target of exosomes and suggests new approaches to treat ischemic stroke. miRNAs differentially expressed in exosomes derived from NSCs at various differentiation stages were detected by high-throughput sequencing for miRNAs. The impacts of miR-9a-5p upregulation were assessed on the differentiation of NSCs. The effects of exosomes derived from normal NSCs and NSCs with up-regulated miR-9a-5p on cell survival and differentiation and AMPK activation were investigated in vitro and in vivo. The high-throughput sequencing analysis revealed that miR-9a-5p was differentially expressed in NSC-derived exosomes at various stages of differentiation. MiR-9a-5p upregulation in exosomes promoted cell differentiation of NSCs. Furthermore, it can sensitized the AMPK signaling pathway. Following deprivation/reperfusion of oxygen-glucose, the differentiation of NSCs was restored, and exosomes significantly reduced cell apoptosis. MiR-9a-5p exosomes reduced the blood-brain barrier permeability and the infarct volume of rats with ischemic stroke in vivo. Neural cell apoptosis was reduced, thus indicating that miR-9a-5p could inhibit the cell apoptosis in vivo. AMPK activation was induced and increased in the MACO/R rat with miR-9a-5p exosomes. MiR-9a-5p exosomes could promote AMPK phosphorylation, increase NSC survival and enhance cell differentiation; this could inhibit the progression of ischemic stroke by maintaining an adequate number of neural cells and promoting endogenous NSC differentiation.

Publisher

American Scientific Publishers

Subject

Pharmaceutical Science,General Materials Science,Biomedical Engineering,Medicine (miscellaneous),Bioengineering

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