Spinal cord injury (SCI) damages long projecting axons leading to loss of sensory and motor function. Permanent disability results because injured axons in the spinal cord fail to regenerate, leaving them disconnected from their targets. There are currently no therapies to restore mobility and sensation following SCI. Therefore, a better understanding of the cellular and molecular mechanisms that compromise axon regeneration after SCI is needed to develop new strategies to restore function. Sensory dysfunctions and neuropathic pain are often the consequences of SCI. Sensory neurons are located in dorsal root ganglia (DRG) and are pseudo unipolar: in addition to a peripherally projecting axon that receive sensory information, they extend a centrally-projecting axon into the spinal cord that transmit this information to the brain. Whereas injury to the peripheral axon elicits a regenerative response, injury to the central axon fails to do so. Regeneration failure has been attributed in part to the weak regeneration- associated gene (RAGs) response upon injury. However, previous studies have assessed changes in gene expression using whole lumbar DRG after SCI, but only proprioceptors and low threshold mechanoreceptors (LTMRs) ascend the spinal cord and are injured after thoracic or cervical SCI. Furthermore, neurons are outnumbered by glial cells and other cell types within DRG, which may also contribute to the failed regeneration after SCI. Because of this remarkable heterogeneity in cell types, analyses of the neuronal and non-neuronal responses to injury has remained a challenge. Therefore, whether and how sensory neurons and the surrounding cells respond to SCI remains unclear. Based on our preliminary studies, we have now reason to believe that SCI results in gene expression changes in proprioceptors and LTMRs that have little overlap with those of peripheral injury, potentially constituting a roadblock for regeneration. The indirect effects of SCI on the non-neuronal cellular environment in the DRG also remain largely unexplored. Using transcriptional analysis at the single cell resolution, we identified a pro-regenerative role of the glial cells that envelop the neuronal soma, known as satellite glial cells. Our goal is now to use single cell transcriptional approaches to unravel how distinct sensory neuron subtypes and the surrounding non-neuronal cells respond to SCI. These approaches may lead to new therapeutic targets to promote axon regeneration and treat neuropathic pain after SCI.
Spinal cord injury (SCI) damages long projecting axons leading to loss of sensory and motor function and remains a major unmet medical need with no current satisfactory treatments. Because of the remarkable cellular heterogeneity in the DRG tissue that contains sensory neurons, analyses of the neuronal and non- neuronal responses to SCI has remained a technical challenge. The proposed studies will use transcriptional approaches with single cell resolution to unravel how different sensory neuron subtypes and non-neuronal cells respond to SCI, which may lead to new therapeutic targets to promote axon regeneration after SCI.
