Ushering in a New Regeneration Strategy
Despite the success of the bridging strategies, a barrier awaits the regrowing axons at the point where the bridges end. In order to make functional connections with the nerve circuits beyond the bridge, the growing nerve fibers must leave the supportive bridge and grow into the “hostile” spinal cord environment. As Martin Schwab, Ph.D., in Zurich, and others have shown, the spinal cord environment contains proteins that stop regenerating axons. Schwab and colleagues are attempting to overcome this inhibition using antibodies that prevent the axons from seeing these stop signals.
Bunge and her colleague, Almudena Ramon-Cueto, M.D., Ph.D., who took time from her laboratory in Spain to work at the Miami Project, reported results of trying a different approach. Using the basic guidance channel model, they transplanted a second type of helper cell just outside the bridges. These helper cells, called olfactory ensheathing glia (EG), are found only in nerves that carry odor sensations to the brain. EG share some characteristics with Schwann cells, including some of their growth-promoting properties, but they may also express traits that resemble astrocytes, a helper cell in the CNS that can inhibit axon growth. Unlike either cell type, EG also migrate extensively within the CNS.
Throughout life, EG usher growing axons across the barrier between the peripheral nerve environment and the brain. The research team was encouraged when they found that EG can also usher long nerve fiber growth into surviving spinal cord regions beyond the end of a Schwann cell bridge. Six weeks after grafting, they traced axons growing through, and far beyond the end of the Schwann cell bridges. Moreover, and quite unexpectedly, the tracer was also found in cells on the opposite side of the bridge. This indicated that these cells had regenerated through the bridge and over an inch farther through the spinal cord tissue, i.e, almost all the way to the brain.
How did the axons grow past the border and through the hostile spinal cord environment? The investigators showed that the EG did not stay near the ends of the grafts, but migrated throughout the Schwann cell cables and spinal cord, accompanying growing axons all the way. In fact, the EG formed a second bridge around the guidance channels, which some axons chose to cross instead of entering Schwann cell cables.
“Schwann cells hold great potential to enhance repair in the spinal cord, because we can now grow large numbers of these cells in the laboratory,” said Bunge. “Our new results show that ensheathing glia could help overcome the barrier that forms between bridges of growth-promoting Schwann cells and the host spinal cord. They appear to escort the growing axons toward spinal cord nerve cells awaiting signals blocked by the injury.”
Reports from other laboratories support the promise. Geoffrey Raisman, M.D., Ph.D., working in London, also found evidence that EG are an important strategy for improving regeneration. His group used EG to stimulate the growth of nerve fibers from the cerebral cortex past a very small area of damage in their spinal cord pathway. Although the exact connections made by the regrowing axons are not yet known, these investigators also reported that the EG accompany the growing fibers. Importantly, the ability of the rats to use their forepaw in a reaching task significantly improved, indicating that some functional connections must have been made.
The extensive migration of the EG and accompanying axons in spinal cord tissue is an important finding. Dr. Ramon-Cueto, who established techniques for isolating EG cell populations, had previously shown that EG injected into spinal cord could usher regenerating sensory axons into the cord past the normally inhibitory peripheral nerve/spinal border. She also made advances in preparing very pure populations of EG and expanding their numbers (hence their availability) during her visit to the Bunge laboratory. Her newest studies are testing the behavioral recovery achieved after this unprecedented regrowth of nerve fibers.
The potential for promoting spinal cord regeneration using specialized cell populations seems brighter than ever. In a related work, Bunge and her colleagues tested Schwann cells genetically modified to secrete brain derived neurotrophic factor (BDNF), which allowed nerve fibers to cross a completely cut spinal cord. The BDNF promoted the growth of some brain cells, but not others. Recent studies from Ithak Fisher’s laboratory in Pennsylvania show BDNF-secreting cells stimulate growth well enough to improve some deficits in leg function. Other laboratories have reported the stimulation of spinal regeneration using other factors, or stimulated immune system cells.
The success of Bunge’s EG experiment appears to lie in the combination of the two types of cell transplanted at the site of spinal cord injury.
Researchers are now looking with great hope to combination strategies to restore significant function in spinal cord injured animals. Such strategies, if proven to be reliable and effective, hold great promise to ultimately be part of new clinical treatments. The goal of the research team now is to improve axonal growth beyond the grafts so that functional connections can be made with the uninjured nerve cells in the host spinal cord.
Dr. Bunge’s future goals are sharply focused, “We hope to demonstrate that growth into the host spinal cord can serve to restore some function, that is, voluntary movement or return of sensation below the injury,” she says. Research underway to fulfill that promise gives researchers confidence to assert that paralysis truly can be reversed.
(Reprinted with permission of The Miami Project to Cure Paralysis, [C], University of Miami.)
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