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NEW STUDY SHOWS STEM CELLS CAN NAVIGATE
SPINAL CORD A new study by researchers with The Robert Packard Center for ALS Research at Johns Hopkins shows that a basic hurdle in restoring function to severely damaged central nervous systems--getting motor neurons to migrate through the spinal cord--may be overcome in rats, using properly directed stem cells. An account of the work, funded by the Packard Center and other patient advocacy groups, appears in this month’s issue of the Proceedings of the National Academy of Sciences. The team of scientists led by neurologist Douglas Kerr, M.D., Ph.D., first coaxed embryonic stem cells (ES cells) into stages just short of becoming motor neurons by applying agents that naturally encourage that sort of thing in utero. The resulting motor neurons-in-training carry necessary cues for their proper positioning in the spinal cord. Then, the researchers injected the committed cells into spinal cords of paralyzed adult rats. They eased them into the spinal cord’s ventral gray matter, an area typically rich in motor neuron cell bodies. “We transplanted roughly 12,000 cells per animal,” says Kerr, “and about 4,000 of them ‘took.’ They became true motor neurons and looked gorgeous.” The trouble was, however, that they didn’t extend their axons through the spinal cord and out to muscle targets. That, according to scientists who research repair of nerve injuries, is a major problem. Kerr was aware of studies showing that myelin, the nerve cell insulator, potently inhibits axon growth. And spinal cords are ringed by myelinated neurons. Scientists have recently uncovered molecules can block myelin’s effect, however. So the team implanted the rats with a pump to drip myelin “de-squelchers” in the vicinity of the animals’ spinal cords. As a result, motor neurons extended themselves through the cord to a key motor neuron way station just outside it, the ventral root. “We think that getting them to travel properly through the cord is the major hurdle,” Kerr says. “It’s significant that axons from these motor neurons make it to the periphery.” He explains that studies on human nervous system injury find damage to peripheral motor neurons—those beyond the spinal cord—far more reversible than spinal cord injury. Cut peripheral nerves, for example, frequently regrow to their muscle targets if the chemical environment is favorable. “This work lays an important early foundation for techniques that we hope will restore function to nervous systems damaged by ALS, spinal motor atrophy (SMA), and other degenerative motor neuron diseases,” says Jeffrey Rothstein, M.D., Ph.D., who directs the Packard Center. Rothstein was also on the research team. Kerr cautions that much remains to be done. The process is “somewhat inefficient,” he says. Only 90 axons made it through the spinal cord. Also, it’s notable that none of the motor neurons extended much beyond the cord— a necessity in restoring ability to move. “These limitations in length are real,” he adds. “We’ve overcome a repulsive cue in the system. Now we need an attractive one.” The team is experimenting with several neural growth factors in an effort to get motor neurons to migrate to muscle. Further, the studies were done with rodent stem cells in rodent tissues. To approach therapy, Kerr says, human ES cells are necessary, “and that’s difficult politically.” Current easily-funded and available human ES cells have been grown on media containing mouse cells. “That makes them unavailable for human therapy.” Kerr stresses that they attempted the animal experiment only after lab work made it look feasible. Their preliminary test-tube studies shed light on “conversations” between their ES-derived motor neurons and healthy muscle cells. By exposing the two cell types to each other, they watched the rise—within hours—of agents both nerve and muscle create to pave the way for their “hookup.” In the lab dishes, Kerr saw the new motor neurons grow outward toward the muscle cells and form proper synapses with proper receptors. The nerve cell-connected muscles even began to contract in the laboratory dish. This new set-up using ES-derived motor neuron cells offers a rare potential for studying motor neuron disease, says Kerr. Its simplicity should let scientists track what goes wrong with neurons with new ease. Already, Kerr is culturing muscle cells with ES cells taken from mouse models of ALS and SMA. He hopes to plot what goes wrong and when at the molecular level. “We should be able to see where normal molecular pathways are disrupted in these models of motor neuron disease.” The study was funded by the Families of SMA, Andrew’s Buddies/Fight SMA, the Robert Packard Center for ALS Research at Johns Hopkins, MDA and the Katie Sandler Fund for Research at Johns Hopkins. Others on the research team are James Harper, Chitra Krishnan, Deepa
Deshpande, Schonze Peck, Irina Shats, and Stephanie Backovic of Hopkins’
Department of Neurology. Jessica Darman is with the Department of Molecular
Microbiology and Immunology with Hopkins’ Bloomberg School of Public
Health. Kerr has a co-appointment in that department. |
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