By Jeffrey Perkel
Thursday, June 5, 2008 12:00 AM
THURSDAY, June 5 (HealthDay News) -- Researchers report they have used neural stem cells to correct a congenital brain disorder in mice.
Dr. Steven Goldman, of the University of Rochester Medical Center in New York, and his colleagues used a type of neural stem cell called "glial progenitor cells" (GPCs), derived from human fetuses, to correct both behavioral and physiological abnormalities in a mouse model of a myelin-deficiency disorder.
The study represents "a very important advance," said Dr. James Goldman, an investigator in the Columbia Neural Stem Cell Program at Columbia University Medical Center, who was not involved in the study.
Though Steven Goldman and others previously had shown that injection of GPCs into mouse brains could lead to remyelination of demyelinated neurons, that observation did not include any change in disease progression.
"The fact that they were able to get at least some of these animals to survive, and show that physiologically and behaviorally they are doing well, is an advance," said James Goldman.
The findings were reported in the June issue ofCell Stem Cell.
Myelin is a structure, comprised of protein and fat, that envelops long neuronal fibers called axons. Axons are the conduits for neural impulses, both conscious and unconscious. Just as electrical cable must be insulated to prevent signal loss over distance, myelin ensures that nerve impulses can traverse long axonal processes in the central nervous system without degrading.
Myelin is formed by neural support cells called oligodendrocytes, which are derived from GPCs. Disorders that arise from the absence or degradation of myelin represent a "substantial proportion of adult neurological diseases," said Steven Goldman. They run the gamut, from autoimmune disorders like muscular dystrophy, to lysosomal storage diseases like Tay-Sachs, to congenital defects like Pelizaeus-Merzbacher Disease, an X-linked condition where myelin doesn't form.
In this study, Goldman and his team used "shiverer" mice, whose congenital lack of myelin basic protein causes them to shake and seize uncontrollably, giving them their name. They typically die by 5 months of age.
The shiverer mice were crossed with immunodeficient mice, so they would not reject the GPC transplant, and split into three treatment groups; 59 received no treatment, 29 received injections of buffer into five different locations in the brain shortly after birth, and 26 received injections of GPCs.
By about 130 days after birth, all 88 control mice died. But six of 26 transplanted animals survived at least 160 days, and four lived over a year. Behaviorally and physiologically, these survivors appeared largely cured, and post-mortem analysis of these animals' brains and spinal cords demonstrated why.
"The entire central nervous system had remyelinated and looked normal in terms of structural configuration of the myelination, both at the microscopic and submicroscopic level, and at the behavioral level," Goldman said.
In other words, from five separate injection sites, the GPCs migrated throughout the central nervous system, differentiated into oligodendrocytes, and began producing myelin.
The researchers then assessed the physiological effect of that remyelination, by measuring the speed of nerve transmission along remyelinated axons. They observed velocities on par with those of normal mice.
"That is proof in principle that putting glial progenitors in a brain like this will at least partially remyelinate the brain, and do so functionally," said James Goldman.
Though this study involved a congenital pediatric disorder, Steven Goldman said his goal is to apply the technique to adult diseases like multiple sclerosis. For now, his team is working to understand why most transplanted animals still die. He suggested this could stem from the seizures that plague shiverer animals, including transplant recipients that have not yet completed remyelination, and said he is exploring the utility of pairing transplants with anticonvulsant therapy to alleviate this problem.
But James Goldman pointed out that before this transplant procedure can be turned into a clinical therapy, several issues must be addressed, not the least of which is the politically sensitive problem of obtaining and using human fetal tissue as a therapeutic agent.
For more on leukodystrophies, visit the U.S. National Library of Medicine.
SOURCES: Steven Goldman, M.D., Ph.D., Dean Zutes Chair, professor, Neurology and Neurosurgery, chief, Division of Cell and Gene Therapy, and co-director, Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, N.Y.; James E. Goldman, M.D., Ph.D., professor, pathology, and director, Division of Neuropathology, Columbia University College of Physicians and Surgeons, New York City; June 2008,Cell Stem Cell