Extracellular vesicles derived from mesenchymal stem cells containing microRNA-381 protect against spinal cord injury in a rat model via the BRD4/WNT5A axis

Abstract

Aims Non-coding microRNA (miRNA) in extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) may promote neuronal repair after spinal cord injury (SCI). In this paper we report on the effects of MSC-EV-microRNA-381 (miR-381) in a rodent model of SCI. Methods In the current study, the luciferase assay confirmed a binding site of bromodomain-containing protein 4 (BRD4) and Wnt family member 5A (WNT5A). Then we detected expression of miR-381, BRD4, and WNT5A in dorsal root ganglia (DRG) cells treated with MSC-isolated EVs and measured neuron apoptosis in culture by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. A rat model of SCI was established to detect the in vivo effect of miR-381 and MSC-EVs on SCI. Results We confirmed an interaction between miR-381 and BRD4, and showed that miR-381 overexpression inhibited the expression of BRD4 in DRG cells as well as the apoptosis of DRG cells through WNT5A via activation of Ras homologous A (RhoA)/Rho-kinase activity. Moreover, treatment of MSC-EVs rescued neuron apoptosis and promoted the recovery of SCI through inhibition of the BRD4/WNT5A axis. Conclusion Taken altogether, miR-381 derived from MSC-EVs can promote the recovery of SCI through BRD4/WNT5A axis, providing a new perspective on SCI treatment. Cite this article: Bone Joint Res 2021;10(5):328–339.

The Effect of miRNA-Modified Exosomes in Animal Models of Spinal Cord Injury: A meta-Analysis

“…The process of study selection is outlined in Figure 1 . A total of 153 articles were identified, of which 11 articles satisfied the inclusion criteria ( Ji et al, 2019 ; Kang et al, 2019 ; Yu et al, 2019 ; Kang et al, 2020 ; Liu et al, 2020 ; Wang et al, 2020 ; Jia et al, 2021 ; Jiang and Zhang, 2021 ; Zhang L. et al, 2021 ). After deleting duplicate articles, we excluded 74 irrelevant articles (e.g., irrelevant disease models, reviews, and conferences) by examining the title and abstract of the article.…”

“…Several studies reported intravenous administration of the same dose of exosomes (100 μg, 200 µg). The studies used many different miRNAs to modify exosomes, including miR-26a ( Chen et al, 2021 ), miR-126 ( Huang et al, 2020 ), miR-145-5p ( Jiang and Zhang, 2021 ), miR-381 ( Jia et al, 2021 ), miR-21 ( Ji et al, 2019 ; Kang et al, 2019 ), miR-216a-5p ( Liu et al, 2020 ), miR-421-3p ( Wang et al, 2020 ), miR-29b ( Yu et al, 2019 ) and miR-181c ( Zhang M. et al, 2021 ).…”

“…Overall, the mean effect of delayed treatment was more significant than immediate treatment in terms of motor function recovery. Jia ( Jia et al, 2021 ) was not included in the subgroup analysis owing to treatment duration was unknown. The results, however, should be interpreted with caution because of the small sample size and the lack of direct evidence.…”

Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury

“…Here, we introduced the involvement of lncRNAs and miRNAs through the Rho/ROCK pathway in IS and SCI and the potential therapeutic effects of the intervention with these ncRNAs. The clinical utility of miRNAs will be very high if they can be delivered in the form of extracellular vesicles, as shown by Jia et al [ 123 ]. Because previous studies on the relationship between the Rho/ROCK pathway and ncRNAs in IS and SCI were only related to apoptosis, neuroinflammation, oxidative stress, and axonal regeneration, future studies are expected to include BBB integrity, astrogliosis, neurogenesis, and angiogenesis.…”

“…Extracellular vesicles (EVs) are candidates for the vehicles of bioactive molecules, such as mRNA, miRNAs, and lncRNAs, and EVs derived from various cells are thus expected to be a potential therapeutic method. Jia et al investigated whether miR-381 encapsulated in the EVs derived from mesenchymal stem cells (MSCs) can promote the recovery of SCI [ 123 ]. MiR-138 is essential for the proliferation of nerve cells during SCI.…”