 |
 |
The Scientist 14[23]:20, Nov. 27, 2000 http://www.thescientist.com/yr2000/nov/research_001127.html Precursor Cells to the Rescue? Two reports out this month suggest that less-than-fully differentiated cells--whether embryonic or adult--could help humans recover from a host of nervous system ailments, ranging from motor neuron diseases to brain cancer. In a study announced at the Society for Neuroscience meeting in New Orleans Nov. 4-9, researchers from Johns Hopkins University School of Medicine and Harvard Medical School infected rodents with Sindbis virus, which causes limb paralysis by attacking the motor neurons that thread from the spinal cord to the muscles. The team then injected embryonic germ cells (EGCs), primordial cells that are pluripotent like stem cells, into the cerebrospinal fluid (CSF) at the base of the animals' spines. The EGCs were pretreated with growth factors to nudge them onto the path of neural differentiation, thereby preventing them from developing into tumors. Within several weeks, the EGCs had migrated to the ventral horn of the spinal cord, which contains the cell bodies of motor neurons. And by eight weeks after injection, 11 out of 18 animals had regained the ability to place the soles of one or both of their hind feet on the ground. Yet, only about 6 percent of the migrating EGCs seemed to have differentiated into neurons, as indicated by expression of cell-surface markers. Earlier animal studies showed that applying stem cells to the site of a traumatic spinal-cord injury leads to some functional recovery. The newly reported experiments were the first involving a diffuse disease that affects the whole spinal cord and the first in which primordial cells were delivered via CSF, according to lead researcher Douglas A. Kerr, an assistant professor of neurology at Hopkins. In ongoing work, "We're trying to characterize why the animals recovered," he says. "And we're also trying to trick the cells prior to implantation into really thinking that they are to be motor neurons. Presumably then we might even see a better functional recovery." Before Kerr and his colleagues turned to EGCs, their study used human neural stem cells (NSCs) derived from a fetus' telencephalon by Evan Y. Snyder, an assistant professor of neurology at Harvard Medical School.1 Kerr recalls that these NSCs restored some function to a handful of rodents, but that they showed no effect in later experiments on a larger group of animals. Snyder and a Harvard team, meanwhile, used the same NSCs in a newly published study on brain cancer.2 After the researchers implanted glioblastoma cells into rodents, the animals developed intracranial tumors. NSCs, which were implanted several days later, infiltrated and surrounded the tumors, and chased down malignant cells that were migrating into normal tissue. Tumor targeting occurred even when the NSCs were introduced far from a tumor, such as into the vein of an animal's tail. When NSCs expressed cytosine deaminase, an enzyme that converts a non-toxic pro-drug into a chemotherapeutic agent, one mouse's tumor shrank about 80 percent. The researchers found that the NSCs neither differentiated nor turned tumorigenic in the recipient rodents. One message of the study, says Snyder, is that "if there's pathology, not only can there be very dramatic, extensive [NSC] migration, but it happens along nonstereotypical, unpredicted pathways." Why do NSCs track brain tumor cells? He suggests some possibilities: Some oncologists view brain-tumor cells as NSCs "gone bad," and these two similar cell types might respond to the same cues. In addition--or alternatively--tumors or the brain cells that they're killing might secrete factors that attract stem cells. Snyder and his colleagues have been holding talks with the Food and Drug Administration about using NSCs as adjunctive therapy to treat brain tumors, which are now almost always incurable. He notes that NSCs could be equipped with transgenes that fight cancer by promoting differentiation or blocking angiogenesis. --Douglas Steinberg References 1. J.D. Flax et al., "Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes," Nature Biotechnology, 16:1033-9, 1998. 2. K.S. Aboody et al., "Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas," Proceedings of the National Academy of Sciences, 97:12846-51, Nov. 7, 2000. *********************