May 24, 2000 St. Louis, May 23, 2000 — After stormy weather, linesmen come out in force to replace electrical insulation. Now scientists have trained a workforce of cells to go into the injured spinal cord and rewrap the lines. Using simple and inexpensive techniques, they turned embryonic stem cells into nervous system cells called oligodendrocytes. When the oligodendrocytes were injected into the spinal cord of injured or mutant rats, they reinsulated naked nerve axons. These long arms of nerve cells carry messages up and down the spinal cord.
"This is the first demonstration that oligodendrocytes derived from embryonic stem cells can remyelinate in the injured adult nervous system," says John McDonald, M.D., Ph.D. "That is relevant because conditions that result in myelin loss, such as spinal cord injury, stroke, multiple sclerosis and transverse myelinitis, occur mainly in adults."
McDonald is an assistant professor of neurology and neurological surgery at Washington University School of Medicine in St. Louis. His research group reports its results in the May 23 issue of Proceedings of the National Academy of Sciences.
Myelin is the fatty material that insulates the nervous system’s communication lines. These lines, formed by axons, allow the brain to communicate with the rest of the body. But they stop working if they lose their myelin, as often happens when the spinal cord is damaged. "Remyelinating otherwise intact axons might be a practical way of helping spinal-cord patients improve functions such as bladder control or limb movement," McDonald says.
Embryonic stem cells can develop into any type of cell in the body. But David I. Gottlieb, Ph.D, professor of neurobiology and associate professor of biochemistry and molecular biophysics, previously discovered that a well-timed application of retinoic acid persuades them to become precursors of nervous-system cells: neurons, astrocytes and oligodendrocytes. In the current study, McDonald’s team showed that oligodendrocytes in these mixed cultures wrap the axons of the neurons with myelin. Moreover, axons were tightly wrapped by nine days — about a month sooner than when oligodendrocytes taken from the brain or spinal cord remyelinate axons of cultured neurons.
The researchers also obtained the first nearly pure cultures of oligodendroctyes from the mouse embryonic stem cells. The trick, they discovered, was to transfer the mixed cultures from medium containing serum to medium containing oligodendrocytes’ preferred growth factors. In a final step, they added medium that had been used by immature oligodendrocyte precursor cells and therefore contained substances the cells had secreted. About 90 percent of the resulting cells were oligodendrocytes.
Further experiments showed that oligodendrocytes from both the mixed cultures and the nearly pure cultures can survive and go to work in living animals. First, the researchers transplanted mixed cultures into rats whose thoracic spinal cord had been injected with a demyelinating chemical three days previously. They labeled the mouse cells in various ways to distinguish them from rat cells.
A week after transplantation, they detected mouse cells in the damaged region. Most of these cells had become oligodendrocytes, presumably in response to signals from the demyelinated cord. Moreover, these oligodendrocytes were functional. "We found very rapid myelination," McDonald says. "We even saw tightly wrapped axons within a week after transplantation."
The researchers transplanted the nearly pure cultures of oligodendrocytes into the spinal cords of shiverer mice. Because these animals are unable to make a key component of myelin called myelin basic protein, their axons get wrapped only loosely. By nine days after transplantation, the mouse oligodendrocytes had migrated several millimeters from the injection site. By a month, some of the axons were tightly wrapped in 10 to 15 layers of myelin, transmission electron microscopy revealed.
"These studies demonstrate that oligodendrocytes derived from embryonic stem cells can myelinate axons in culture and can survive and myelinate axons in adult animals with defective or injured spinal cords," McDonald says. "Therefore, transplants of myelin-producing cells may offer a pragmatic approach to restoring meaningful neurological function. And the methods we have developed can produce unlimited supplies of such cells."
Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S, Holekamp TF, McDonald JW. Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. Proceedings of the National Academy of Sciences, May 23, 2000.
Grants from the National Institute of Nervous Disorders and Stroke, the W.M. Keck Foundation and NFL Charities supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.
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