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New Packard Center Animal Studies Shed Light on Nerve Regeneration, Suggest Approach During World War II, soldiers with injuries to legs or other outlying parts of the nervous system tended to separate easily into the lucky or the unlucky. The lucky ones got quick medical treatment and severed nerve ends were sewn back together. The less fortunate had to wait longer for surgery or didn’t get it at all; they lost nerve function permanently. “With the peripheral nervous system and chronic nerve injury, there’s a window of opportunity you must catch if you’re to have an effect,” says Packard Center scientist Ahmet Höke. Now, Packard studies into the basis for that window suggest that they could, at some point, translate into repair, not only for people with nerve trauma but also for those with chronic neurodegenerative diseases like ALS. After patients experience the damaging effects of ALS, their nerves appear similar to those Höke observes in laboratory models where outlying nerves are surgically severed. Once the vital relationship between a nerve cell’s axons and targeted muscle fibers is chronically disrupted—by disease or injury—the axons start to disintegrate. Höke has studied this process, charting how long it takes and what’s happening within the neuron. Most important, he and his team have worked out how long separated axons still “have what it takes” to operate normally should they somehow become reunited with muscle targets. To stay whole, axons need regular exposure to growth factors and other nurturing agents that they receive from muscle. When that connection’s gone, Höke and colleagues have found, neurons start becoming unable to regenerate. “You can see loss even after eight weeks,” Höke says. “It’s fairly complete by six months.” What keeps axons going even that long, Höke has found, is the temporary nurture by surrounding Schwann cells. When axons are damaged, nearby Schwann cells secrete sustaining growth factors for a time. Eventually, they, too, atrophy and the nurture stops. Recently, Höke’s team at Johns Hopkins, where he’s a researcher, surveyed the Schwann cells’ useful agents. On top was pleiotropin, a small, hormone-like messenger that appeared in large amounts about a week after axon damage. To see if pleiotropin might sustain injured axons or even help them re-grow toward targets, Höke undertook lab studies on cultures of rodent spinal cord sections—a usual model for testing nerve-saving or nerve-encouraging agents. Pleiotropin indeed encouraged growth of motor axons to the point that they grew outside the spinal cord. “You never see this normally,” he said. Axons usually stop growing at the spinal cord border. That fact is especially interesting in light of studies by other Packard scientists in which stem cells injected into rat spinal cords could morph into neurons and send axons outward, though barely out of the spinal cord. Getting “replacement” neurons to travel to muscle targets is high on ALS researchers’ wish lists. Höke’s next step involved whole-animal tests. With pleiotropin-secreting cells in the vicinity, his team witnessed clear regeneration of axons across a gap in rodents’ severed sciatic nerves. “Now,” he says, “we want to see if we can get them to grow consistently to the right target.” Höke and postdoctoral fellow, Ruifa Mi, presented their studies at last November’s Society for Neuroscience meetings in San Diego. |
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