Extracellular vesicles derived from bone marrow mesenchymal stem cells alleviate neurological deficit and endothelial cell dysfunction after subarachnoid hemorrhage via the KLF3-AS1/miR-83-5p/TCF7L2 axis

Meixiong Cheng; Ling Liu; Tian Zhang; Yong Chen; Qi Wang; Yaqiu Wu

doi:10.1016/j.expneurol.2022.114151

Extracellular vesicles derived from bone marrow mesenchymal stem cells alleviate neurological deficit and endothelial cell dysfunction after subarachnoid hemorrhage via the KLF3-AS1/miR-83-5p/TCF7L2 axis

Exp Neurol. 2022 Oct:356:114151. doi: 10.1016/j.expneurol.2022.114151. Epub 2022 Jun 20.

Authors

Meixiong Cheng¹, Ling Liu¹, Tian Zhang¹, Yong Chen¹, Qi Wang², Yaqiu Wu³

Affiliations

¹ Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, PR China.
² Department of Neurosurgery, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, PR China. Electronic address: wangqi@med.uestc.edu.cn.
³ Department of Neurosurgery Intensive Care Unit, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, PR China. Electronic address: wuyaqiu@med.uestc.edu.cn.

PMID: 35738418
DOI: 10.1016/j.expneurol.2022.114151

Abstract

Background: New data are accumulating on the effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in cerebrovascular diseases. We explored the potential role of KLF3-AS1-containing bone marrow MSC-EVs (BMSC-EVs) in a rat model of subarachnoid hemorrhage (SAH).

Methods: A rat model of SAH was established by endovascular perforation method, into which KLF3-AS1-containing EVs from BMSCs or miR-183-5p mimic were injected. Further, brain microvascular endothelial cells (BMECs) were induced by oxyhemoglobin (OxyHb) to simulate in vitro setting, which were co-cultured with KLF3-AS1-containing EVs from BMSCs. Effects of KLF3-AS1 on neurological deficits in vivo and endothelial cell dysfunction in vitro were investigated. We also performed bioinformatics analysis to predict downstream factors miR-183-5p and TCF7L2, which were verified by RIP, RNA pull-down and luciferase activity assays.

Results: BMSC-EVs was demonstrated to alleviate neurological deficits in SAH rats and endothelial cell dysfunction in OxyHb-induced BMECs. In addition, BMSC-EVs were shown to deliver KLF3-AS1 to BMECs, where KLF3-AS1 bound to miR-183-5p and miR-183-5p targeted TCF7L2. In vivo results confirmed that BMSC-EVs regulated the KLF3-AS1/miR-183-5p/TCF7L2 signaling axis to attenuate neurological deficit and endothelial dysfunction after SAH.

Conclusion: Overall, KLF3-AS1 delivered by BMSC-EVs upregulate TCF7L2 expression by binding to miR-138-5p, thus attenuating neurological deficits and endothelial dysfunction after SAH.

Keywords: Bone marrow mesenchymal stem cells; Extracellular vesicles; KLF3-AS1; Subarachnoid hemorrhage; TCF7L2; microRNA-183-5p.

Publication types

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

MeSH terms

Animals
Endothelial Cells / metabolism
Extracellular Vesicles*
Mesenchymal Stem Cells* / metabolism
MicroRNAs* / genetics
MicroRNAs* / metabolism
Rats
Subarachnoid Hemorrhage* / metabolism

Substances

MIRN138 microRNA, rat
MicroRNAs