Abstract
BackgroundSpinal cord injury (SCI) has a very disabling central nervous system impact but currently lacks effective treatment. Bone marrow-derived macrophages (BMDMs) are recruited to the injured area after SCI and participate in the regulation of functional recovery with microglia. Previous studies have shown that M2 microglia-derived small extracellular vesicles (SEVs) have neuroprotective effects, but the effects of M2 BMDM-derived sEVs (M2 BMDM-sEVs) have not been reported in SCI treatment.ResultsIn this study, we investigated the role of M2 BMDM-sEVs in vivo and in vitro for SCI treatment and its mechanism. Our results indicated that M2 BMDM-sEVs promoted functional recovery after SCI and reduced neuronal apoptosis in mice. In addition, M2 BMDM-sEVs targeted mammalian target of rapamycin (mTOR) to enhance the autophagy level of neurons and reduce apoptosis. MicroRNA-421-3P (miR-421-3p) can bind to the 3′ untranslated region (3′UTR) of mTOR. MiR-421-3p mimics significantly reduced the activity of luciferase-mTOR 3′UTR constructs and increased autophagy. At the same time, tail vein injection of inhibitors of SEVs (Inh-sEVs), which were prepared by treatment with an miR-421-3p inhibitor, showed diminished protective autophagy of neuronal cells in vivo.ConclusionsIn conclusion, M2 BMDM-sEVs inhibited the mTOR autophagy pathway by transmitting miR-421-3p, which reduced neuronal apoptosis and promoted functional recovery after SCI, suggesting that M2 BMDM-sEVs may be a potential therapy for SCI.
Highlights
Spinal cord injury (SCI) has a very disabling central nervous system impact but currently lacks effective treatment
We found that mammalian target of rapamycin protein levels decreased after treating cells with M2 bone marrowderived macrophage (BMDM)-Small extracellular vesicles (sEVs)
Scale bar: 20 μm. c Flow cytometry analysis of the macrophage markers on M2 BMDM, macrophage markers (CD11b) and M2 macrophage specificity markers (CD206) are highly expressed (**p < 0.01, ***p < 0.001). d QRT-PCR results of macrophage markers in induced M2 BMDM. e A schematic diagram of the extraction of BMDM-sEVs. f Morphology of BMDM-sEVs was observed by transmission electron microscopy (TEM)
Summary
Spinal cord injury (SCI) has a very disabling central nervous system impact but currently lacks effective treatment. Several studies have shown that sEVs can enter the injured area after spinal cord injury and produce a significant therapeutic effect [12,13,14]. Related research indicates that peripheral immune cells, especially M1 macrophages, enter the spinal cord after injury and produce deleterious effects. Depleting macrophages or enhancing the repair macrophage phenotype (M2 macrophages) can increase axon growth and improve motor function recovery [16, 17]. It is unclear whether sEVs derived from M2 macrophages can attenuate SCI
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