ROBUST FUNCTIONAL REGENERATION BEYOND THE GLIAL SCAR
Jerry Silver, PhD, Professor, Department of Neurosciences, Case Western Reserve University
Over the past several years, we have concentrated our efforts learning whether molecules that glia produce to generate normal axon boundaries in the embryo are re-expressed by reactive astroglia in the scar that develops after injury. One of the most interesting families of extracellular matrix molecules, the proteoglycans, were first discovered by my lab to be major players in creating developmental as well as regenerative glial boundaries. We developed in vitro assays using gradients of proteoglycans that, like the in vivo glial scar, create dystrophic endings on regenerating adult axons. This result taught us that it was not just the presence of proteoglycans in the scar that was important for growth inhibition but also their spatial patterning. This breakthrough enabled us, for the first time, to begin to dissect the molecular and cellular machinery of this unusual axonal ending and learn why axons in a dystrophic state undergo long distance retraction from the lesion epicenter, how they interact with other types of cells, such as stem cells, inflammatory cells or CNS macroglia and how axons in the dystrophic state can be re-energized into a growth state. Our ultimate goal is to develop strategies to overcome inhibitory molecules and axonal dieback after injury in order to promote functional regeneration. An exciting development is our recent demonstration that combining (1) a long segment of autologous peripheral nerve as a “bridge” to bypass a hemisection lesion of the adult rat spinal cord with (2) inhibitory matrix modification via chondroitinase at the PNS/CNS interfaces allows regenerating axons to exit the bridge, form functional synapses, and restore useful movement to the once paralyzed limb and robust functional recovery to the diaphragm. This new strategy shows clearly, for the first time, that long distance regeneration, with appropriate re-formation of functional connections, can be achieved in the adult after spinal cord injury.