Exosome-Mediated miR-21 Was Involved in the Promotion of Structural and Functional Recovery Effect Produced by Electroacupuncture in Sciatic Nerve Injury

Abstract

Purpose. Our study is aimed at investigating the mechanism by which electroacupuncture (EA) promoted nerve regeneration by regulating the release of exosomes and exosome-mediated miRNA-21 (miR-21) transmission. Furthermore, the effects of Schwann cells- (SC-) derived exosomes on the overexpression of miR-21 for the treatment of PNI were investigated. Methods. A sciatic nerve injury model of rat was constructed, and the expression of miR-21 in serum exosomes and damaged local nerves was detected using RT-qPCR after EA treatment. The exosomes were identified under a transmission electron microscope and using western blotting analysis. Then, the exosome release inhibitor, GW4869, and the miR-21-5p-sponge used for the knockdown of miR-21 were used to clarify the effects of exosomal miR-21 on nerve regeneration promoted by EA. The nerve conduction velocity recovery rate, sciatic nerve function index, and wet weight ratio of gastrocnemius muscle were determined to evaluate sciatic nerve function recovery. SC proliferation and the level of neurotrophic factors were assessed using immunofluorescence staining, and the expression levels of SPRY2 and miR-21 were detected using RT-qPCR analysis. Subsequently, the transmission of exosomal miR-21 from SC to the axon was verified in vitro. Finally, the exosomes derived from the SC infected with the miR-21 overexpression lentivirus were collected and used to treat the rat SNI model to explore the therapeutic role of SC-derived exosomes overexpressing miR-21. Results. We found that EA inhibited the release of serum exosomal miR-21 in a PNI model of rats during the early stage of PNI, while it promoted its release during later stages. EA enhanced the accumulation of miR-21 in the injured nerve and effectively promoted the recovery of nerve function after PNI. The treatment effect of EA was attenuated when the release of circulating exosomes was inhibited or when miR-21 was downregulated in local injury tissue via the miR-21-5p-sponge. Normal exosomes secreted by SC exhibited the ability to promote the recovery of nerve function, while the overexpression of miR-21 enhanced the effects of the exosomes. In addition, exosomal miR-21 secreted by SC could promote neurite outgrowth in vitro. Conclusion. Our results demonstrated the mechanism of EA on PNI from the perspective of exosome-mediated miR-21 transport and provided a theoretical basis for the use of exosomal miR-21 as a novel strategy for the treatment of PNI.

Schwann cells-derived exosomal miR-21 participates in high glucose regulation of neurite outgrowth

“…Moreover, the inhibition of exosomal miR-21 eliminated the protective effects of neurons via the AKT pathway ( Gao et al., 2020 ). Our previous results also showed that SC-derived exosomal miR-21 promoted neurite outgrowth in vitro ( Liu et al., 2022a , 2022b ), while upregulation of miR-21 in MSCs-derived exosomes can also inhibit neuronal apoptosis ( Xu et al., 2019 ). Together with results from in vivo studies ( Wang et al., 2020a ), we believe that SC-derived exosomal miR-21 is involved in the pathogenesis of DPN and may be a promising target for DPN treatment.…”

“…Multiple miRNAs were down- and upregulated in diabetes, and have been shown not only to play an important role in the pathogenesis of T2D ( Moura et al., 2014 ; Ozdemir and Feinberg, 2019 ) but also to be potential biomarkers for the development and progression of T2D as estimated by their circulating levels ( Dehwah et al., 2012 ). Recent studies have reported that miR-21 is involved in regulating T2D glucose metabolism by promoting insulin secretion, further revealing the potential mechanism of miR-21 in regulating the pathogenesis of DPN ( Liu et al., 2022a , 2022b ). As a widely studied miRNA molecule, miR-21 was found to be closely related to peripheral neuropathy ( Karl et al., 2022 ).…”

“…Many studies have supported the roles of exosomes in intercellular communication through paracrine signaling in DPN ( Singh et al., 2021 ; Fan et al., 2020 ). As essential components of exosomes, miRNAs have attracted much attention in exosomal function studies ( Liu et al, 2022b ; Fan et al., 2021 ). Additionally, in vitro data showed that SC-derived exosomes promoted neurite outgrowth of DPN.…”

The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS

“…Next, the hsa-miR-200c-3p, related to PTPRD and TBK1 ( Table 3 and Figure 3 ), was found to be a key factor that promotes successful spinal cord regeneration in axolotls, regulating the stem cell identity [ 123 ]. The hsa-miR-21-5p, related to KIFAP3, was recently shown to be involved in the promotion of structural and functional recovery in sciatic nerve injury [ 124 ]. The hsa-miR-222-3p, related to COG2, KIF5C, and KIF3B ( Supplementary Table S1 , Table 3 , and Figure 3 ) enhanced the neuronal differentiation of neural stem cells and thus the combination of nanofibrous scaffolds with miR-222 is proposed as a promising approach for neural tissue regeneration [ 125 ].…”

Electroacupuncture Improves Intestinal Motility through Exosomal miR-34c-5p Targeting SCF/c-Kit Signaling Pathway in Slow Transit Constipation Model Rats

“…It has been reported that exosomal miR-34c-5p regulates ICC in STC model rats by targeting SCF. Besides, electroacupuncture (EA) can regulate exosomes, exosomal miRNAs, and exosomal circRNAs [ 14 , 15 ].…”