Global Replacement of Brain Cells by Neural Stem Cells Reported

In the June 8, 1999 issue of the Proceedings of the National Academy of Sciences, researchers at Harvard Medical School and Children's Hospital (Boston, MA) report findings that may provide hope for suffers of a variety of neurological diseases. Using neural stem cells, Evan Snyder, lead author of the study, effected global replacement of non-functional brain cells in a mouse strain unable to myelinate cells. This result extends the potential use of neural stem cells beyond diseases that affect limited regions of the brain, like Parkinson's disease.

Previous work from Snyder's laboratory had shown that neural stem cells, delivered through intracerebroventricular injection, could supply therapeutic proteins throughout the brain. Mice lacking ß-gluocuronidase, a model for human neurodegenerative lysosomal storage diseases, had their enzyme levels restored by transplanted neural stem cells engineered to produce the missing enzyme.

In this study, Snyder and his colleagues injected cultured neural stem cells into the brain ventricles of newborn mice harboring the shiverer mutation, so-called because it causes mice to develop severe tremors by 2 to 3 weeks of age. The tremor develops because the mice lack myelin basic protein, (MBP) resulting in global demyelination of brain neurons. This condition mimics the defect seen in some human demyelinating disorders, such as multiple sclerosis and childhood disorders called leukodystrophies. The researchers found that the transplanted cells migrated throughout the brain and matured into normal-looking oligodendrocytes, the brain cells that produce myelin. These oligodendrocytes produced a significant amount of the missing protein and covered adjacent nerve fibers with myelin. Moreover, tremors disappeared almost completely in 60% of the tested mice that received the transplants.

The researchers also report that the stem cells produced more oligodendrocytes when transplanted into the brains of mutant mice than when transplanted into normal mice, suggesting that the neural stem cells somehow sensed that something was missing in the mutant mice and compensated for the problem. This ability to compensate for missing cell types could make neural stem cells a more effective therapy than previously thought.

Snyder believes that it may also be possible to genetically engineer neural stem cells so that they not only replace lost cells throughout the brain—as is seen in Alzheimer's disease—but also produce proteins that correct the defect leading to neuronal death. "Sometimes the original cells are overly sensitive to stress from toxins, viral infections, or other problems because of missing or damaged genes. If so, transplanted cells with normal genes could withstand the stress," says Snyder. "Researchers also can engineer neural stem cells to withstand, neutralize, or even protect other cells against a toxin or other threat."

Dr. Snyder is now testing neural stem cells in animal models for a variety of disorders, including perinatal asphyxia, which can lead to cerebral palsy; Krabbe's disease, another demyelinating disorder; and stroke. These studies could eventually lead to clinical trials.

For more information: Evan Y. Snyder, Assistant Professor of Neurology and Pediatrics, Harvard Medical School, Division of Newborn Medicine, 300 Longwood Avenue, Boston, MA 02115. Tel: 617-355-6070. Fax: 617-738-1542. Email: snyder@a1.tch.harvard.edu.