Objective Regeneration of corticospinal tract (CST) axons after spinal cord injury (SCI) is a key element in rebuilding neuronal connections to restore voluntary motor function. However, it remains challenging owing to limited effective interventions. This study adopted a modified transcranial optogenetic technique to stimulate CST axon regeneration into the injury site of completely transected SCI and explore the underlying molecular mechanisms.
Methods A novel optogenetic light emitting diode (LED) device was used to stimulate the brain motor cortex in channelrhodopsin-2–yellow fluorescent protein (ChR2-YFP) transgenic mice to observe the regeneration of CST axons in the injury site of a complete SCI. The LED device was also used In vitro to stimulate the motor cortex slices of the transgenic mouse brain for observing the outgrowth of their neurites.
Results After transcranial optogenetic stimulation, the pyramidal neurons of bilateral cerebral motor cortices, in ChR2-YFP transgenic mice were activated, CST axons regenerated into the injury site of the spinal cord, and the motor function of the paralyzed hindlimbs improved. Proteomic analysis revealed that CST axon regeneration was associated with the activation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the cerebral motor cortices. In vitro LED blue light illumination enhanced the outgrowth of neurites from the brain slices of transgenic mice. Treatment with a JAK2/STAT3 inhibitor led to a significant attenuation of neurite outgrowth.
Conclusion The modified transcranial optogenetic technique stimulated bilateral motor cortices, in the brains of ChR2-YFP transgenic mice. It increased the excitability of pyramidal neurons in the motor cortices, and promoted CST axon regeneration by activating the JAK2/STAT3 pathway, repairing complete SCI.
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Objective Herein, we investigated whether mesenchymal stem cells (MSCs) transplantation combined with electroacupuncture (EA) treatment could decrease the proportion of proinflammatory microglia/macrophages and neurotoxic A1 reactive astrocytes and inhibit glial scar formation to enhance axonal regeneration after spinal cord injury (SCI).
Methods Adult rats were divided into 5 groups after complete transection of the spinal cord at the T10 level: a control group, a nonacupoint EA (NA-EA) group, an EA group, an MSC group, and an MSCs+EA group. Immunofluorescence labeling, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blots were performed.
Results The results showed that MSCs+EA treatment reduced the proportion of proinflammatory M1 subtype microglia/macrophages, but increased the differentiation of anti-inflammatory M2 phenotype cells, thereby suppressing the mRNA and protein expression of proinflammatory cytokines (tumor necrosis factor-α and IL-1β) and increasing the expression of an anti-inflammatory cytokine (interleukin [IL]-10) on days 7 and 14 after SCI. The changes in expression correlated with the attenuated neurotoxic A1 reactive astrocytes and glial scar, which in turn facilitated the axonal regeneration of the injured spinal cord. In vitro, the proinflammatory cytokines increased the level of proliferation of astrocytes and increased the expression levels of C3, glial fibrillary acidic protein, and chondroitin sulfate proteoglycan. These effects were blocked by administering inhibitors of ErbB1 and signal transducer and activator of transcription 3 (STAT3) (AG1478 and AG490) and IL-10.
Conclusion These findings showed that MSCs+EA treatment synergistically regulated the microglia/macrophage subpopulation to reduce inflammation, the formation of neurotoxic A1 astrocytes, and glial scars. This was achieved by downregulating the ErbB1-STAT3 signal pathway, thereby providing a favorable microenvironment conducive to axonal regeneration after SCI.
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Objective This study aimed to identify differentially expressed genes (DEGs) by transcriptome analysis to elucidate a potential mechanism by which governor vessel electroacupuncture (GV-EA) promotes neuronal survival, axonal regeneration, and functional recovery after complete transection spinal cord injury (SCI).
Methods Sham, control, or GV-EA group adult female Sprague Dawley rats underwent a complete transection SCI protocol. SCI area RNA-seq investigated the DEGs of coding and noncoding RNAs 7 days post-SCI. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were used to classify DEGs functions, to explain a possible molecular mechanism. Immunofluorescence and BBB (Basso, Beattie, and Bresnahan) score were used to verify a GV-EA treatment effect following SCI.
Results GV-EA treatment could regulate the expression of 173 mRNA, 260 lncRNA, and 153 circRNA genes among these DEGs resulted by SCI. GO enrichment analysis showed that the DEGs were most enriched in membrane, actin binding, and regulation of Toll-like receptor signaling pathway. KEGG pathway analysis showed enriched pathways (e.g. , Toll-like receptors, MAPK, Hippo signaling). According to the ceRNA network, miR-144-3p played a regulatory role by interacting with lncRNA and circRNA. GV-EA also promoted the injured spinal cord neuron survival, axonal regeneration, and functional improvement of hind limb locomotion.
Conclusion Results of our RNA-seq suggest that post-SCI GV-EA may regulate characteristic changes in transcriptome gene expression, potential critical genes, and signaling pathways, providing clear directions for further investigation into the mechanism of GV-EA in subacute SCI treatment. Moreover, we found that GV-EA promotes neuronal survival, nerve fiber extension, and motor function recovery in subacute SCI.
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Spinal cord injury (SCI) is a result of a devastating injury to the central nervous system. Currently, there is no effective treatment available for these patients. The possible use of mesenchymal stem cell (MSC)-based treatment for SCI has been the focus of extensive investigations and is increasingly moving from the bench to bedside. Both experimental observations and clinical studies have shown the safety and efficacy of MSCs in managing SCI. However, the exact mechanism by which MSCs contribute to the repair of the injured spinal cord remains to be elucidated. In this review, we aim to summarize current research findings about the role of MSCs in improving complex pathology after SCI. MSCs exert a multimodal repair mechanism targeting multiple events in the secondary injury cascade. Our recent results showing the perineurium-like differentiation of surviving MSCs in the injured spinal cord may further the understanding of the fate of transplanted MSCs. These findings provide fundamental support for the clinical use of MSCs in SCI patients. Under experimental conditions, combining novel physical, chemical, and biological approaches led to significant improvements in the therapeutic efficacy of MSCs. These findings hold promise for the future of cell-based clinical treatment of SCI.
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