July 16, 1999 Neuroscientists at Case Western Reserve University's School of Medicine, examining how nerve cell regrowth is affected by degenerating spinal cord tissue, have published a new study showing tremendous capacity for nerve fiber regeneration from transplanted adult nerve cells in adult spinal cords with large lesions.
When nerve fibers in the spinal cord are severed, they are no longer able to relay signals to other parts of the nervous system. The segment of the nerve fiber beyond the cut that is no longer connected to the nerve cell dies. The remaining live piece still connected to the cell body fails to regrow past the site of injury and, because of this, the person remains permanently paralyzed and unable to feel sensation below the damaged area.
While the research was not designed to restore function in the test animals, their work demonstrates an important new basic principle that the damaged spinal cord has, in fact, a far greater potential for nerve regeneration than had ever been thought possible. Their work further points the finger at molecules in scar tissue at the direct site of injury as being the major obstacle to spinal cord regeneration.
In the July 15 issue of the Journal of Neuroscience, Stephen J.A. Davies, Jerry Silver, and colleagues at CWRU report that they transplanted sensory nerve cells from adult, green fluorescent mice into the damaged spinal cord of rats.
The spinal cord, specifically the dorsal column sensory pathways, had been cut with a knife. The adult nerve cells, which carry their own fluorescent marker, were transplanted from the mice into the degenerating spinal cord tissue beyond the direct site of injury in host rats. This was accomplished by using a micro-transplantation technique developed by Davies which itself causes no further damage to the rat spinal cord.
"Nobody would have put money on these nerve cells regenerating," said Silver, a professor of neurosciences at CWRU. However, what they saw excited them. "This paper shows the most robust and efficient regeneration of nerve cell axons (that is, fibers) in the chronically injured spinal cord to date."
The scientists saw great growth in three sets of experiments following transplantation: at the same time as injury (acute injury), two weeks following an injury (subchronic), and, most exciting of all, at three months following injury (chronic). The nerves grew about 1 millimeter daily, which is considered fast, in either direction from the transplant location, but stopped upon reaching scar tissue at the site of the cut in the spinal cord.
Silver explained that the current, dominating theory holds that both normal as well as injured adult white matter tracts in the spinal cord are overtly inhibitory because they contain molecules within the myelin sheaths that signal nerve fibers not to grow.
"One might suspect that the added amount of damage to the white matter pathways in our study, all that degeneration and inflammation, would produce a nerve fiber pathway potently inhibitory for nerve growth," he said. "But we saw scads of axons," said Silver. "Amazingly, after a full three months, there is still potential for regeneration away from the injury."
When the researchers looked at the lesion site, they saw proteoglycan molecules, which Silver's laboratory has strongly correlated in past studies with the cessation of axon growth. In this study, Davies said, "Not only do the regenerating axons stop upon reaching the scar, but they change the shape of their tips and become 'dystrophic' with malformed endings. This is the hallmark of regeneration failure."
Silver said, "The cell body of an injured nerve does try to regenerate its axon, but it gets stuck. The debate over the last two decades has centered around the issue of what stops nerve fiber regeneration, myelin or scar tissue? We're showing that if you take adult nerve cells and free them from the proteoglycan-laden scar environment, they rapidly regrow fibers. This paper offers compelling evidence that the scar itself is the major impediment to regeneration. Also, the white matter past the area of injury that's dying and changing, is not changing in a way that inhibits regeneration."
Silver and Davies suggest that their study offers hope that removing or overcoming the molecular obstacles in the scar may unlock a far greater potential for nerve regeneration in the spinal cord than had previously been thought possible.
The study was supported by the National Institute of Neurological Diseases and Stroke, the Daniel Heumann Fund, the Brumagin Memorial Fund, and the International Spinal Research Trust. Others authors were David R. Goucher and Catherine Doller of the CWRU School of Medicine's Department of Neurosciences.
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