Intraspinal transplantation of fetal central nervous system (CNS) tissue or segments of peripheral nerve (PNS grafts) has demonstrated the ability of these implants to sustain axonal growth from CNS and PNS neurons following acute injury. The chronically injured spinal cord is a second lesion model with obvious clinical relevance, yet it is not known if neurons associated with longstanding CNS lesions retain the capacity for axonal growth or whether the encapsulating glial scar characteristics of a chronic lesion site impedes the course of regrowing axons. Since our previous studies have shown that fetal spinal cord (FSC) tissue survives transplantation into chronic lesion cavities, the exciting possibility that a neural tissue transplantation approach could provide an appropriate model system to study the regenerative potential of neurons in the chronically injured spinal cord can now be addressed. The proposed research will use quantitative morphometric techniques, immunocytochemistry and electron microscopy to test the hypothesis that implanted FSC tissue has the ability (1) to modify the encapsulating glial scar associated with a chronic lesion cavity and (2) to prevent the reformation of a partitioning glial scar following re-injury of the spinal cord (Specific Aim I). Experiments using immunocytochemical and neuroanatomical tracing techniques will map the pattern and extent of graft-host axonal integration to determine if chronically injured neurons retain the potential for axonal growth and if this potential can be enhanced by grafts of fetal CNS or PNS tissue (Specific Aim II) or by a conditioning lesion and removal of glial scar tissue prior to transplantation (Specific Aim III). The importance of this research is at least threefold: (1) it will establish whether the dense glial scarring that results after CNS injury can be modified to facilitate apposition and integration of graft and host tissues; (2) it will help define the substratum requirements necessary for the initiation and maintenance of axonal growth across an extensive lesion site; and (3) it will indicate the ability of neurons in the chronically injured spinal cord to regrow their axons and determine if this capacity for growth can be stimulated by transplantation paradigms involving either fetal CNS or PNS tissues. The experiments outlined in this proposal will define the potential for axonal regeneration and structural repair of the chronically injured spinal cord, thus forming the basis for future experiments related to the long term goal of re-establishing structural and functional continuity across a longstanding lesion in the spinal cord by the use of neural tissue transplantation techniques.
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