Human Neural Stem Cells Advance Distant Prospect Of Reseeding Damaged Brain

Last November, Snyder did. Snyder, an assistant professor of neurology at Children's Hospital and Harvard Medical School, and his colleagues reported in Nature Biotechnology that they had cloned a human neural stem cell-one of the first times a human stem cell was identified in a solid organ. Moreover, the researchers confirmed that the human cells held the same potential for future therapies as that established for their rodent counterparts.

Snyder will present his work in a press briefing on January 25 at the annual meeting of the American Association for the Advancement of Science in Anaheim, Calif.

Snyder's study validates a decade's worth of research into the cell biology of brain development in mice. It also moves current attempts at harnessing neural stem cells for the treatment of human disease one step closer to reality. Conditions ranging from inherited neurogenetic defects, such as Tay-Sachs disease, to birth-related oxygen deprivation, spinal cord damage, and brain cancer could one day be treated with neural stem cells, says Snyder.

For some of these disorders, grafting mouse cells into mouse brains has been known for some time to succeed, but a lack of human cells for study delayed such research in the human brain.

Snyder's paper came amid a recent flurry of stem cell reports. Researchers elsewhere showed the existence of immature cells in the embryonic human brain, while others demonstrated continued birth of nerve cells in small regions of the adult human brain. And two teams described the cloning of human embryonic stem cells that can generate cells of all tissue types, fueling the intertwined debates about the ethics of human cloning and fetal tissue research.

Earlier work in the field from a small group of laboratories including Snyder's indicated that the brain might harbor stem cells much like those that hematologists have known for decades to reside in the bone marrow. The bone marrow stem cell can renew itself and give rise to all the circulating blood and immune cells. It can even repopulate an immune system wiped out by irradiation in a bone marrow transplant.

In principle, researchers could try to develop an analogous treatment-wholesale repopulation of brain areas from stem cells-if only they could lay their hands on a neural stem cell with similar abilities. That, says Snyder, would expand the current paradigm of neural transplantation-which generally involves adding fetal tissue to a small area of nerve degeneration-to the broader goal of "reseeding" the entire brain with progenitors that would then take their cues from the existing brain and mature into whatever cell type was needed, wherever it was needed. This way, diseases might eventually be treated that neurotransplantation cannot yet address, says Snyder. These include large-scale brain defects such as stroke or multi-infarct dementia, multifocal diseases such as multiple sclerosis or even global defects wrought by some genetic and dementing diseases, he adds.

In this study, the scientists removed cells from deep within the forebrain of one aborted fetus several years ago. When they cloned individual cells, they gave rise to both neurons and their support cells, the glia. Next they grafted immature stem cells into different areas of the developing mouse brain. Following signals from their new environment, the human stem cells migrated along existing pathways and matured into the type of neuron and glia appropriate for the particular area.

The researchers inserted the gene for a color-producing protein to recognize the human cells embedded in the mouse tissue, raising hope that human stem cells could also be engineered to express therapeutic genes, as was shown in mice.

To explore further the stem cells' therapeutic potential, the scientists showed that-in culture-enzyme-producing human stem cells were able to correct the deficiency underlying Tay-Sachs disease. This suggests the human cells could supply therapeutic proteins missing in so-called single-gene-or even multi-gene-inherited brain diseases. Finally, the scientists found that the stem cells restored a brain area in mutant mice whose cerebellar granule neurons do not develop properly.

In all those experiments, the grafted cells integrated seamlessly into the surrounding brain tissue, says Snyder. Even so, he does not know if they actually function. To address this crucial question, the scientists are working on disease models in which they can test whether the animal regains a lost ability.

Another caveat lies in whether the grafted cells will cause an immune response in the human host. Though previous rodent work suggests they will not, this question remains unanswered.

Several years of research still separate this study from the first experiments on humans. Next, Snyder's group will study the human cells in animal models of human diseases, including spinal cord injury and brain damage resulting from oxygen starvation. In preliminary work, he and his collaborators have injected the cells into monkey fetuses to explore the possibility of in utero or early postnatal cell therapy.

Much research into "embryonic" stem cells remains hobbled by ethical concerns that keep in place a ban on Federal funding for work with human embryonic tissue. Snyder's work, however, remains largely outside of this debate because he has turned a single sample of fetal tissue into stable cell lines. In fact, his work received National Institute of Neurological Disorders and Stroke funding to develop alternatives to the use of fetal tissue. "We think we have done that," he says.

The Harvard team included postdoctoral fellows Jonathan Flax and Sanjay Aurora, together with lab manager Chunhua Yang, all at Children's Hospital, Richard Sidman, from the New England Regional Primate Research Center in Southborough, Mass., and scientists from three other institutions.