MIR-17-92 cluster enriched msc exosomes promote myelination and axonal extension which contribute to increased EMG conduction and functional recovery after stroke in rats

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Introduction: MiR-17-92 cluster enriched exosomes derived from multipotent mesenchymal stromal cells (MSCs) increase neural plasticity and functional recovery after stroke. Here, we investigate the mechanisms underlying this functional recovery. Methods: Rats (n=10) subjected to 2h of transient middle cerebral artery occlusion (MCAO) were intravenously administered control liposomes and exosomes (100 μg total exosome protein/rat) derived from MSCs infected with miR-17-92 expression lentivirus (Exo-miR-17-92 ) and control lentivirus (Exo-Con) at 24h post stroke. Threshold currents of intracortical microstimulation on the contralateral cortex for evoking impaired forelimb movements were measured 4 weeks after stroke, followed with biotinylated dextran amine (BDA) injection to anterogradely label the corticospinal tract. The cervical cord (C4-7) was processed for vibratome longitudinal sections for BDA-labeled axon measurement at 6 weeks post MCAO. The myelination in the central nervous system (CNS) was indicated by Luxol fast blue stain. In vitro cultured rat organotypic brain slices were employed to further investigate whether the PTEN/PI3K/Akt/mTOR pathway mediates the effect of miR-17-92 enriched exosomes on increasing myelination. Results: Compared to the liposome treatment, Exo-Con treatment significantly reduced the threshold current (47.8±8.67 mA vs 54.9±6.49 mA, p<0.05), increased BDA-labeled contralesional axons sprouting into the denervated spinal cord and re-myelination in the CNS (p<0.05, respectively). Exo-miR-17-92 treatment enhanced the restorative therapeutic effects compared with that from EXO-Con treatment (40.9±5.71 mA, p<0.05, respectively). In vitro data showed that Exo-miR-17-92 significantly increased myelination of neurons, and the induced myelination significantly reduced by applicating of inhibitors for the PI3K/Akt/mTOR pathway (p<0.05, respectively). Conclusions: Our studies suggest that the enhanced neurological functional recovery after treatment of stroke with the miR-17-92 cluster enriched MSC exosomes may be attributed to the increase of the axonal extension and re-myelination of neuronal axons, and possibly via PTEN mediated activation of the PI3K/Akt/mTOR pathway.




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