Neural progenitor cell (NPC) transplantation has high therapeutic potential in neurological disorders. Functional restoration may depend on the formation of reciprocal connections between host and graft. While it has been reported that axons extending out of neural grafts in the brain form contacts onto phenotypically appropriate host target regions, it is not known whether adult, injured host axons regenerating into NPC grafts also form appropriate connections. We report that spinal cord NPCs grafted into the injured adult rat spinal cord self-assemble organotypic, dorsal horn-like domains. These clusters are extensively innervated by regenerating adult host sensory axons and are avoided by corticospinal axons. Moreover, host axon regeneration into grafts increases significantly after enrichment with appropriate neuronal targets. Together, these findings demonstrate that injured adult axons retain the ability to recognize appropriate targets and avoid inappropriate targets within neural progenitor grafts, suggesting that restoration of complex circuitry after SCI may be achievable.
This work was supported by the Craig H. Neilsen Foundation, the US Veterans Administration Gordon Mansfield Spinal Cord Injury Consortium, the National Institutes of Health (NS042291), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
Identifying appropriate neural stem cell grafts to stimulate regeneration of the corticospinal axons after injury (in an animal model) could most closely predict human benefit to this vitally important motor system. This is a collaborative endeavor between six research groups working closely together to accelerate understanding and discovery of therapies for SCI.