Cellular responses underlying functional recovery following spinal cord injuryPublic Deposited
Spinal cord injury causes devastating and frequently irreversible loss of neurological function. Although injured central nervous system neurons have the intrinsic ability to regenerate, the environment in the damaged spinal cord is non-permissive. The goal of this thesis was to explore the cellular and molecular mechanisms that limit recovery after SCI, and to develop new techniques for modifying the milieu within the damaged spinal cord to facilitate recovery. The fundamental hypothesis underlying these studies was that therapeutic alteration of the extracellular matrix (ECM) within the damaged spinal cord would facilitate regeneration and functional improvement. Our first set of studies examined the effects of injection into the injured spinal cord of a peptide amphiphile that self-assembled to provide a scaffold permissive for regeneration. We found that injection of this material reduced glial scarring, promoted motor and sensory regeneration, and improved locomotor function. We next examined the mechanisms underlying the functional recovery and found an increase in serotonin fibers caudal to the injury site. Since serotonin signaling is known to enhance locomotor activity after SCI, it is likely that this ingrowth of serotonergic fibers participated in the partial restoration of function. We next utilized neural differentiated mouse embryonic stem cells to deliver a neurotrophic factor to the injury site and found this approach to be of little benefit after severe SCI. In the last portion of this study, we describe the relationship between the chemokine, SDF1, and its receptor, CXCR4, in the normal spinal cord and post injury to explore potential new biochemical and cellular loci for therapeutic intervention after SCI. Overall our findings suggest that therapeutic approaches such as ours that reengineer the ECM have the potential for facilitating regeneration and promoting functional recover after SCI.
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