Neural Progenitor Cells for Mitigating Pain after Spinal Cord Injury
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abstract
Following spinal cord injury (SCI), structural and physiological changes in nociceptive circuitry result in central sensitization of dorsal horn neurons, partially because of the loss of local and descending presynaptic inhibitory inputs to these neurons. Restoring modulatory inputs to this circuitry may therefore require the provision of new neurons that can integrate into injured circuits and restore balance to how pain signaling is gated. However, little is still understood about the exact populations of dorsal horn neurons that become hyper-responsive to pain, and precisely what presynaptic inputs onto these neurons are lost. This is in large part because it has previously been difficult to study nociceptive circuitry in isolation.We have recently found that neural progenitor cell (NPC) grafts can support functionally appropriate innervation by the injured host sensory nervous system. Mounting evidence that both injured host neurons and newly grafted neurons can spontaneously innervate their correct targets supports the possibility that dysfunctional circuitry can be modulated via transplantation of phenotypically correct subtypes of neurons. With specific regard to the modulation of dysfunctional sensory processing, inhibitory projections from grafts may be required to dampen disinhibited nociceptive activity in the injured spinal cord. However, the specificity of connections made by grafted neurons onto host nociceptive neurons is currently unknown.We hypothesize that transplantation of spinal cord NPC grafts into sites of SCI will restore inhibitory inputs onto dorsal horn pain-processing neurons at and below the site of injury, thereby attenuating hyperactive nociceptive signaling. We will characterize the identities of NPC graft-derived neurons that are monosynaptically connected with host dorsal horn pain-processing circuitry. In addition, we will selectively silence distinct populations of inhibitory graft-derived neurons in order to determine these neurons’ effects on pain-responsive spinal cord neurons, as well as on behavioral pain outcomes. Results of this work will inform our understanding of the mechanisms by which graft-derived spinal cord neurons integrate into and modulate injured spinal cord sensory systems. This will be important in the future development of cell transplantation therapies to treat sensory dysfunction and pain following SCI. (CHN: SCIRTS chn:wdg)
