While most neurons in the adult nervous system are terminally differentiated, olfactory neuroepithelium (One) retains the ability to generate neurons and ensheathment cells throughout life. The long-term goal of project 3 is to develop a procedure by which a victim of spinal cord injury (SCI) or other neurological lesion could provide his/her own donor tissue for regenerative grafts. We have cultured human postmortem One to obtain rapidly dividing cells that form neurospheres, which have been collected and passaged more than 25 times. We hypothesize that progenitors in the neurospheres can promote functional recovery by replacing damaged neurons and ensheathing cells as well as enhancing axonal sprouting and elongation.
The specific aims are (1) to develop and amplify colonies of lineage-restricted neuronal and ensheathment progenitors, (2) to determine if human ONe progenitors enhance functional recovery in SCI rats and (3) to determine the best site(s) in the olfactory mucosa for harvesting progenitors by endoscopic biopsy. Specifically One progenitors will be engrafted in normal and SCI rats to determine their ability to replace lost neurons, stimulate axonal elongation and promote remyelination. Three models will be employed to examine these recovery mechanisms: cervical dorsal hemisection, kainic acid exocitotoxic SCI, and X-irradiated/ethidium bromide myelin deficient spinal cords. The potential health benefit is that One is readily accessible; a patient's own tissue could be us to provide cells for repair of CNS lesions which would eliminate problems associated with graft-host- rejection to provide cells for repair of CNS lesions which would eliminate problems associated with graft-host rejection. And tissue availability. Immunolocalization will evaluate lineage specific markers in One cells exposed to growth factors. Recovery following transplantation will be evaluated by track tracing, electrophysiology, quantitative microscopic morphometry and behavioral assessment. Anatomic mapping of One in situ correlated with in vitro scoring will determine the region of the human nasal cavity that produces the highest yield of specific progenitors as a prerequisite to endoscopic biopsy of patients. These studies will determine the therapeutic utility of One for autologous transplantation to the CNS.
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