Abstract
BackgroundSpinal cord injury (SCI) is a catastrophic injury that can cause irreversible motor dysfunction with high disability. Exosomes participate in the transport of miRNAs and play an essential role in intercellular communication via transfer of genetic material. However, the miRNAs in exosomes which derived from neurons, and the underlying mechanisms by which they contribute to SCI remain unknown.MethodsA contusive in vivo SCI model and a series of in vitro experiments were carried out to explore the therapeutic effects of exosomes. Then, a miRNA microarray analysis and rescue experiments were performed to confirm the role of neuron-derived exosomal miRNA in SCI. Western blot, luciferase activity assay, and RNA-ChIP were used to investigate the underlying mechanisms.ResultsThe results indicated that neuron-derived exosomes promoted functional behavioral recovery by suppressing the activation of M1 microglia and A1 astrocytes in vivo and in vitro. A miRNA array showed miR-124-3p to be the most enriched in neuron-derived exosomes. MYH9 was identified as the target downstream gene of miR-124-3p. A series of experiments were used to confirm the miR-124-3p/MYH9 axis. Finally, it was found that PI3K/AKT/NF-κB signaling cascades may be involved in the modulation of microglia by exosomal miR-124-3p.ConclusionA combination of miRNAs and neuron-derived exosomes may be a promising, minimally invasive approach for the treatment of SCI.
Highlights
Spinal cord injury (SCI) is a catastrophic injury that can cause irreversible motor dysfunction with high disability
M1 microglia were identified by immunofluorescence staining of ionizing calcium binding adaptor molecule 1 (IBA1) and inducible nitric oxide (NO) (INOS)
Exosomes suppressed activation of M1 microglia and A1 astrocytes by delivering miR‐124‐3p in vivo and in vitro Because the present study was able to demonstrate that neuron-derived exosomal miR-124-3p can be transferred to microglia, we further investigated whether miR-124-3p represented a biological messenger between neurons and microglia and could regulate activation of M1 microglia and induced activation of A1 astrocytes
Summary
Spinal cord injury (SCI) is a catastrophic injury that can cause irreversible motor dysfunction with high disability. Exosomes participate in the transport of miRNAs and play an essential role in intercellular communication via transfer of genetic material. The miRNAs in exosomes which derived from neurons, and the underlying mechanisms by which they contribute to SCI remain unknown. Spinal cord injury (SCI) is a traumatic event of life-changing which leads to permanent sensory-motor disabilities, and it is estimated that the mortality rate of hospitalized. In the case of increased BBB permeability, the secretion of chemokines by M1 microglia allow recruitment and infiltration of hematogenous leukocytes which perpetuate the inflammatory response, increasing neuronal death induced by excitotoxicity [11]
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