Using a totally new approach, researchers at the Massachusetts General Hospital (MGH) have for the first time induced the growth of severed adult mammalian spinal cord fibers across the site of the injury. The animal study appearing in the May issue of Neuron is the first to report repairing such an injury without the use of implanted cells or tissues to bridge the severed fibers. In addition, the findings call into question current assumptions about barriers to spinal cord regeneration.
"We have actually tricked nerve cells into growing beyond the area of a spinal cord injury by switching them into an actively growing state," says Clifford Woolf, M.D., Ph.D., of the Neural Plasticity Research Group in the MGH Department of Anesthesia and Critical Care, who led the study. "While the particular approach we used cannot be applied in humans, it points us in a promising new direction. The question is no longer whether spinal cord regeneration is possible but how it will be achieved."
It has been known for years that severed nerve fibers in the adult spinal cord cannot regenerate. However, damaged peripheral nerves - those in the extremities - can heal themselves. What has intrigued and frustrated researchers is the fact that the fibers making up one sensory system in the spinal cord come from the same cells as do the fibers in peripheral nerves. These sensory nerve cells or neurons have two long processes, called axons, that extend from the main cell body located next to the spinal cord. One axon, the central branch, joins the spinal cord and travels to the brain; the other, the peripheral branch, travels out to the extremities. If the peripheral branch of these cells is injured, it regenerates; if the central branch is injured, it does not.
Because two branches of the same cell exhibit totally different healing capacities, most researchers thought the difference must lie in the environments surrounding the branches, which are very different. Previous attempts to repair severed spinal cords focused on implants of peripheral nerve-tissue "bridges," reproducing cellular environments similar to that of peripheral nerves, or grafts made from embryonic spinal cords, which have the capacity to regenerate. The success of those efforts, Woolf says, has been marginal.
In the current study, Woolf and his colleague Simona Neumann, PhD, questioned the assumption that environment made the key difference. "Perhaps, we thought, the question should be whether or not the cell was receiving molecular signals from the injury site to stimulate regenera-tion. Maybe damage to the central branch does not switch on these growth signals, while damage to the peripheral branch does."
To test this hypothesis, the researchers devised a groups of experiments in rats to see whether injury to the peripheral branch of a nerve made a difference to regeneration of the central branch, which would indicate whether molecular growth signals were important. When they injured the peripheral branch of the sciatic nerve (the main sensory nerve to the leg) at the same time as they damaged the animal's spinal cord, the results were striking. Numerous axonal fibers sprouted and grew in the spinal cord around and directly into the injured area. The fibers, which extended from the lower segment of the spinal cord, did not grow all the way across the injury into the upper segment. In comparison, however, damaging the spinal cord without the peripheral nerve injury produced no growth at all into the injured area.
Injuring the peripheral nerve a week before the spinal cord injury produced even more dramatic results. Axonal fibers grew either completely through or around the injured area and some extended into the upper portion of the spinal cord. "A complete regeneration across the injury site had been achieved," Woolf says.
"We have shown that if we can switch these cells into a state where they can grow, they will grow - even the central branch," he adds. "The problem was not that the adult central nervous system is hostile territory for growth, as previously thought. The problem is getting the injured cells to grow. Now we need to identify the molecular signals that induce this growth and the genes on which they act. If we can find ways to turn those signals on without the peripheral nerve injury and apply them soon after patients suffer spinal cord injury, we may finally achieve what was once seen as an unreachable goal: reconnection of a severed spinal cord."
The study was supported by a grant from the International Spinal Research Trust.