| Research Abstract |
Recovery from central nervous system damage in adult mammals is hindered by their limited ability to replace lost cells and damaged myelin, and reestablish functional neural connections. However, recent progresses in stem cell biology are making it feasible to treat spinal cord injury using several cell sources, such as embryonic stem cells, mesenchymal stem cells, and neural stem cells.
First, we transplanted in vitro expanded neural stem/progenitor cells, derived from fetal rat spinal cord into the spinal cord 9 days after contusion injury at the middle of the cervical level, resulting in the functional recovery of skilled forelimb movement. However, it should be noted that the anatomy and function of spinal cord are quite different between rodents and primates, indicating the necessity of pre-clinical model of spinal cord injury using primate animals to develop the cell therapy.
Secondary, we established a primate model of the spinal cord contusion injury, using a common marmoset and
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transplanted in vitro expanded human neural stem/progenitor cells derived from fetal spinal cord. The human neural stem/progenitor cells grafted into primate spinal cord 9 days after injury survived, differentiated into neurons, astrocytes, and oligodendrocytes, and eventually promoted the recovery of motor function after spinal cord injury in primate animals.
Finally, to achieve further regeneration of the damaged axon, we developed the blocking agent to Sema 3A, which is one of the axonal growth inhibitors, and we showed that this agent has a blocking effect against Sema 3A chemorepulsive activity to neurite extension as well as collapse activity to growth cone in vitro. Then we demonstrated the validity of this blocking agent to the rat SCI model. After inducing spinal cord transection injury at Th 8 level in adult S-D rats, we infused the blocking agent or vehicle into the injured spinal cord through an osmotic pump. In the treated group, hindlimb movement was recovered significantly compared to the vehicle-control group, and moreover, GAP-43 positive fibers were observed in its caudal site as well as injured site, which was not observed in the vehicle controls. These findings suggest that blocking of Sema 3A is a potential therapeutic reagent for SCI.
Although there are many problems still unresolved such as scaffold and how to overcome the glial scar formation that prevents the regeneration of injured axons, our findings strongly suggest the feasibility of transplantation neural stem/progenitor cells as therapeutics of human spinal cord injury. Less
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