Targeting Axon Growth from Neuronal Transplants along Preformed Guidance Pathways in the Adult CNS

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Abstract
To re-establish neuronal circuits lost after CNS injury, transplanted neurons must be able to extend axons toward their appropriate targets. Such growth is highly restricted within the adult CNS attributable to the expression of inhibitory molecules and general lack of guidance cues to direct axon growth. This environment typically induces random patterns of growth and aberrant innervation, if growth occurs at all. To target the growth of axons from neuronal transplants, we are using viral vectors to create guidance pathways before neuronal transplantation. In this study, we transplanted postnatal rat dorsal root ganglia neurons into the corpus callosum of adult rats. Replication-incompetent adenoviruses encoding growth or guidance factors were injected along the desired pathway 1 week before cell transplantation, allowing time for sufficient protein expression by host glial cells. With expression of nerve growth factor (NGF) and basic fibroblast growth factor, sensory axons were able to grow along the corpus callosum, across the midline, and toward an NGF-expressing target in either the contralateral striatum or cortex: a distance of 7–8 mm including a 90° turn from white matter into gray matter. Furthermore, expression of semaphorin 3A slightly dorsal and lateral to the turning point increased the number of axons turning into the striatal target. These results show that judicious expression of neuron-specific chemoattractant and chemorepellant molecules using viral vectors can support and target axon growth from neuronal transplants in the adult CNS.