Spinal cord repair breakthrough
Fluorescence image of axons in composite mosaic scans of rodent spinal cord sections. [Sofroniew lab]
Preclinical results from US-based researchers suggest returning nerve cells to a younger state could aid in the repair of spinal cords.
Using deconvolution fluorescence microscopy and scanning confocal laser microscopy to study the spinal cords of mice and rats, Professor Michael Sofroniew from the Brain Research Institute at UCLA and colleagues, discovering three key factors important for helping axons regrow following spinal cord damage.
For many years, researchers have thought that the scar that forms after a spinal cord injury actively prevents damaged neurons from regrowing but by reverting neurons to an earlier growth state, they could overcome this barrier and reconnect severed spinal cord nerves.
Once nerve reconnection had taken place, neurons could be induced to regrow across the scarred tissue.
Axon regeneration in nerve fibres [EPFL]
“There are several growth patterns in the spinal cord that shut down after its development,” explains Sofroniew. “We wanted to see if we could reactivate those patterns following injury and whether that would lead to regrowth of the axons.”
Using both mouse and rat spinal cord injury models, the researchers from UCLA and their collaborators at Harvard Medical School, Boston, and the Swiss Federal Institute of Technology, Lausanne, Switzerland, looked at three components of the regrowth process.
First, they tried to genetically turn back the neurons’ clock by reactivating the growth program that produced the original connections, specifically neurons that look like they are trying to regrow.
While not active in adults, the neurons still carry the program used during early growth.
By injecting viruses containing genes related to this program, the researchers were able to revert spinal cord neurons back to a state where axon growth could occur.
Second, the new axons needed to travel through the damaged tissue.
Normally, growing axons move along highways paved with molecules that are not found in the scar tissue.
After injecting the injury site with a gel containing a combination of growth-promoting proteins, the scientists saw an increase in axon-supportive molecules, effectively providing a “road” across the injury.
Finally, the growing axons needed to exit the injury site and find targets.
During development, neurons release proteins called chemoattractants that axons home in on.
To mimic this, the researchers injected chemoattractant proteins in a trail beyond the injury site and saw that these “chemical breadcrumbs” successfully led axons to grow completely through the injury site.
When any of the three treatments - viral activation of the growth program, formation of the path for axon travel, and the addition of chemoattractants - were not provided, minimal, if any regrowth was seen.
In contrast, when all three were used in the order described, the neurons grew robustly. Tens or hundreds of axons travelled across the scar and reconnected with neurons on the other side.
Although their results suggest that the new connections could conduct electrical signals across the injury, the rodents could not move any better.
However, Sofroniew emphasises that this was not unexpected.
“We would expect that these regrown axons would behave very much like the new axons we see in development,” he says. “Much like a newborn must learn to walk, these newly formed circuits will probably require training before functional recovery can be seen.”
Sofroniew and his colleagues are now looking to continue to refine their understanding of the mechanisms involved in axon regeneration and to determine how newly wired circuits can best be retrained to restore movement.
This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of NIH.
Research is published in Nature.