Scientists have met one of the long-standing challenges of regenerative medicine: For the first time, they have succeeded in coaxing an injured spinal cord to regenerate sensory axons in rats that reinnervate the specific place they would need to reach in order to regain function.

Human vertebral column Image: Gray's Anatomy, via Wikipedia

However, the paper, published online in Nature Neuroscience, showed that the regenerated axons, which also formed synapses, showed little to no activity.

"I think it's impressive what they've found," said John Houle, who studies regeneration after spinal cord injury at Drexel University College of Medicine in Philadelphia. However, he cautioned that the lack of physiological response from the regenerated structures left him "underwhelmed."

Often, scientists researching regeneration achieve anatomical repair without physiological repair, "and then other times we see some behavioral recovery without any anatomical basis," said Houle, who was not involved in the research. For that reason, the community is still a long ways away from having any major impact on spinal cord injury. "I just think we need to be really guarded in how we talk about recovery," he told The Scientist.

Regenerating axons can make potentially millions of connections, and need to reach the right targets in order to regain function. To test whether they could guide this growth to the correct spot, the researchers, led by Mark Tuszynski and first author Laura Taylor Alto at the University of California, San Diego, made lesions in 14 rats' spinal cords two millimeters from the target site -- the nucleus gracilis in the brainstem, one of the relay stations for signals traveling from the spinal cord to the brain.

The authors added a graft of autologous bone marrow stromal cells as scaffolding for the regenerating axons, and injected a lentiviral vector expressing a growth-promoting factor, neurotrophin-3 (NT-3), into the nucleus gracilis, to guide regenerating axons to that specific location.

They found that new axons reinnervated the nucleus gracilis, and boosting the amount of NT-3 increased reinnervation -- to 27% of the innervation present in intact regions. The new axons "grow exactly into the right area," said study author Armin Blesch, also at UCSD. When the researchers directed NT-3 to a different region, the axons grew in that direction.

The axons that reached the nucleus gracilis formed synapses that appeared to resemble normal synapses, but showed little to no activity. The regenerating axons appeared to also have little to no myelin, which may explain the lack of synaptic activity, Blesch suggested. The findings "really show how fundamental [remyelination] is," he said, adding that he and his colleagues did not test whether myelination did, in fact, restore function.

Blesch explained that he and his coauthors decided to do this experiment after previous experiments showed that regenerating axons could grow 2-3 mm following lesions. They therefore decided to figure out if axons covering that distance could reach the right target. "The next step is to see if we can get these [targeted] axons to grow longer," he said, perhaps by adding factors that counteract inhibitors to growth.

The current paper "is an incremental step, and it's an important one, and it just indicates there's much more work to be done," said Houle.

Correction (August 3): When originally posted, the article stated the paper was published in the current issue of Nature Neuroscience. The article is, in fact, an advance online publication. The Scientist regrets the error.


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