UC Davis researchers solve multiple sclerosis brain-cell mystery
Finding key to understanding disease, search for cures
Researchers at UC Davis have discovered the source of cells involved in a phenomenon called reactive astrogliosis, characterized by a large number of enlarged star-shaped cells in the brains and spinal cords of people with multiple sclerosis (MS), Alzheimer's disease and multiple episodes of minor head trauma. In multiple sclerosis, these abnormal cells are found in plaques that damage the myelin sheath that surrounds neurons, impairing their signaling function.
The study is lead by David Pleasure, director of UC Davis' Institute for Pediatric Regenerative Medicine, and offers the first firm evidence to date that, at least in the case of multiple sclerosis, the cells are descendant from normal astrocytes.
"This may not hold true for all diseases, but, in the case of MS, we have a very robust model," said Pleasure, who also is a professor in the Department of Neurology. The study used a widely used mouse-model of MS.
The findings, published in the Aug. 17 issue of The Journal of Neuroscience, used genetic fate- mapping techniques in a mouse model to show that reactive astroglial cells in the MS model were derived from normal astrocytes that had increased in size and number.
The findings are significant because the neurological diseases and injuries in which reactive astrogliosis occurs are also ones for which there are no effective cures. Knowing the origin of the cells, scientists can now compare normal astrocytes with the ones associated with disease and try to figure out what has gone awry.
In multiple sclerosis, these abnormal cells are found in and around plaques in the brain and spinal cord, where there is evidence of damage to myelin sheaths and axons. In patients with Alzheimer's disease or after recurrent head trauma, these abnormal cells are scattered throughout the brain.
"Some say these cells are 'bad guys' that contribute to the pathology of diseases. Some say they are 'good guys' trying to support the neurons under adverse conditions."
The current study does not settle that controversy, but it is an important step in that direction and in the search for cures, Pleasure said.
MS is an autoimmune disease in which a person's own disease-fighting mechanisms attack neurons in the central nervous system, destroying the myelin and, to some degree, the axon -- the long, slender projection of the nerve cell. The disease is characterized initially by episodes of reversible neurologic deficits. In most patients, these episodes are followed by progressive neurologic deterioration over time. The cause of the disease is unknown.
Normal astrocytes, collectively called astroglia, are the 'helper cells' of the central nervous system, offering biochemical support and providing nutrients to neurons found in the brain and spinal cord. Until now, scientists did not know whether the cells found in demyelinating plaques came from other neurological cell types, as at least one study had suggested, or from normal astrocytes.
Fuzheng Guo, the study's first author and a postdoctoral fellow in Pleasure's lab, led the team that conducted the experiments for the current study. The team used genetically engineered mice whose astrocytes express enhanced yellow fluorescent protein when injected with tamoxifen, a synthetic form of the hormone estrogen.
Researchers injected these two- to five-month-old mice with tamoxifen and, 30 to 40 days later, injected them with a protein that causes experimental autoimmune encephalomyelitis, a widely used model for MS. Control mice received sham injections. At regular intervals, the team scored the severity of the multiple sclerosis-like symptoms, such as limping.
The idea was to determine what happened to the normal astrocytes -- as well as any cells that might descend from them via cell division -- as the animals developed the disease.
At the end of the experiment, the team counted and measured astroglial cells in both diseased and control mice. They found, in the gray matter of the brain and spinal cord, only an increase in cell size. In the white matter, they found both an increase in size and number of astrocytes.
The team also conducted similar experiments tracking the fate of other neurological cell types, including oligodendrocyte progentior cells (which give rise to oligodendrocytes that insulate axons) and ependymal cells (which line the cerebral ventricles).
According to Pleasure, the current study will help to guide the search for a cure for MS and other diseases involving demyelination. His lab and others are now repeating these experiments using models of other diseases. They also are taking a closer look at the potential role of astrocytes in those diseases.
"Now, we can, among other things, carefully compare normal and reactive astrocytes to understand what specific changes are happening and then get an idea if those changes are likely to be detrimental or supportive to neurons."
Other authors of the study include, from UC Davis, Chengji Zhou, assistant professor of cell biology and human anatomy; postdoctoral fellows Jiho Sohn and Yazhou Wang; graduate students Yoshiko Maeda, Monica Delgado and Emily Mills and Joyce Ma, a medical student; research associates Laird Miers and Jie Xu; and associate project scientist Peter Bannerman, as well as Hirohide Takebayashi of Japan's Kumamoto University.
The research was supported by grants from the National Institutes of Health, the National Multiple Sclerosis Society, Shriners Hospitals for Children and the California Institute for Regenerative Medicine.