Bone marrow mesenchymal stem cell derived exosomal miR-455-5p protects against spinal cord ischemia reperfusion injury.

At present, much more studies have focused on the therapeutic effect of exosome-delivered microRNAs on diseases. Previous study has shown that miR-455-5p is downregulated in ischemic stroke, but little is known about the role of exosome-delivered miR-455-5p in spinal cord ischemia reperfusion (SCIR) injury. Herein, we isolated exosomes from bone marrow mesenchymal stem cells (BMSCs) transfected with lentivirus vectors containing miR-455-5p. SCIR rat model was established after the intrathecal injection of exosomes containing miR-455-5p. The expression level of miR-455-5p was downregulated after SCIR, administration of exosomal miR-455-5p enhanced the level of miR-455-5p in the injured spinal cord. Hind-limb motor function scores indicated that exosomal miR-455-5p improved the recovery of hind-limb function of SCIR rats. HE staining and Nissl staining showed that miR-455-5p enriched exosomes reduced histopathological abnormalities after SCIR. Double immunofluorescence staining revealed that exosomes containing miR-455-5p reduced apoptosis of neurons, and activated autophagy in neurons after SCIR. We observed that the expression of Nogo-A, a direct target of miR-455-5p, was decreased in the spinal cord of exosomal miR-455-5p administrated SCIR rats. Targeting relationship between miR-455-5p and Nogo-A was verified by dual-luciferase reporter assay. In summary, exosomes containing miR-455-5p had the neuroprotective effects on SCIR injury by promoting autophagy and inhibiting apoptosis of neurons.

Liu B ，Zheng W ，Dai L ，Fu S ，Shi E ... -  《-》

Bone marrow mesenchymal stem cell-derived exosomal microRNA-124-3p attenuates neurological damage in spinal cord ischemia-reperfusion injury by downregulating Ern1 and promoting M2 macrophage polarization.

Li R ，Zhao K ，Ruan Q ，Meng C ，Yin F ... -  《-》

Exosomal miR-9-5p derived from BMSCs alleviates apoptosis, inflammation and endoplasmic reticulum stress in spinal cord injury by regulating the HDAC5/FGF2 axis.

Exosomes derived from human bone marrow mesenchymal stem cells (BMSCs) play potential protective roles in spinal cord injury (SCI). However, the underlying mechanisms remain not fully elucidated. Herein, we isolated exosomes from BMSCs, and exosome morphology and marker protein levels were identified by transmission electron microscopy (TEM) and Western blot, respectively. PC12 cells were treated with lipopolysaccharide (LPS) to construct an injury model, and then incubated with BMSCs-derived exosomes. We found that exosome incubation increased miR-9-5p expression, and inhibited apoptosis and the levels of inflammation cytokines and ER stress marker proteins. Moreover, histone deacetylase 5 (HDAC5) was identified as a target gene of miR-9-5p by dual-luciferase reporter gene assay. Exosomal miR-9-5p upregulated fibroblast growth factor 2 (FGF2) expression by inhibiting HDAC5-mediated FGF2 deacetylation. Then, it was observed that HDAC5 overexpression or FGF2 inhibition reversed the inhibitory effects of exosomal miR-9-5p on apoptosis, inflammation and ER stress in PC12 cells. Additionally, an SCI rat model was established and exosomes were injected for treatment. Exosomal miR-9-5p treatment alleviated locomotor ability, histopathological damage, neuronal apoptosis, inflammation and ER stress in SCI rats. In conclusion, our findings indicated that exosomal miR-9-5p derived from BMSCs promoted FGF2 expression by inhibiting HDAC5-mediated deacetylation, thus inhibiting LPS-induced apoptosis, inflammation, and ER stress in PC12 cells, and alleviating SCI in rat model. Our study may provide a therapeutic direction for SCI.

He X ，Zhang J ，Guo Y ，Yang X ，Huang Y ，Hao D ... -  《-》

Overexpression of miR-338-5p in exosomes derived from mesenchymal stromal cells provides neuroprotective effects by the Cnr1/Rap1/Akt pathway after spinal cord injury in rats.

Growing evidence has shown that microRNAs (miRNAs) play crucial roles in the physiopathology of spinal cord injury (SCI). Recent studies have confirmed that miR-338-5p regulates myelination, suggesting a potential role in the treatment of SCI. However, the molecular mechanism of miR-338-5p on SCI is still unknown. Recently, exosomes have emerged as an ideal vector to deliver therapeutic molecules such as miRNAs. Here, we explored the effects of miR-338-5p-overexpressing exosomes derived from bone marrow-derived mesenchymal stromal cells (BMSCs) on SCI. In vivo, a model of contusion SCI in rats was established, and we observed that overexpression of miR-338-5p in exosomes profoundly increased the expression levels of neurofilament protein-M and growth-associated protein-43 and decreased those of myelin-associated glycoprotein and glial fibrillary acidic protein, which provided neuroprotective effects after acute SCI. In an in vitro study, we found that overexpression of miR-338-5p in exosomes repressed cell apoptosis following H2O2-induced oxidative stress injury in PC12 cells. Additionally, we confirmed that cannabinoid receptor 1 (Cnr1) was the target gene of miR-338-5p by dual-luciferase reporter assays and that Rap1 was the downstream gene by the KEGG pathway analysis. We found that miR-338-5p increased cAMP accumulation as a consequence of downregulated expression of the target gene Cnr1, and then, Rap1 was activated by cAMP. Eventually, the activation of the PI3K/Akt pathway attenuated cell apoptosis and promoted neuronal survival by cAMP-mediated Rap1 activation. In brief, these findings showed that exosomes overexpressing miR-338-5p were a promising treatment strategy for SCI.

Zhang A ，Bai Z ，Yi W ，Hu Z ，Hao J ... -  《-》

Mesenchymal stem cell-derived exosomes containing miR-145-5p reduce inflammation in spinal cord injury by regulating the TLR4/NF-κB signaling pathway.

Jiang Z ，Zhang J 《-》