Insight Into Neural Stem Cells Has Implications For Designing Therapies

Adult neural stem cells give rise to the three major types of brain cells -- astrocytes, oligodendrocytes and neurons. Their role in producing neurons is of particular interest to scientists because neurons orchestrate brain functions -- thought, feeling and movement. If scientists could figure out how to create specific types of new neurons, they potentially could use them to replace damaged cells, such as the dopamine-producing neurons destroyed in Parkinson's disease.

In recent years, scientists have determined that adult neural stem cells are located primarily in two regions of the brain -- the lining of the brain's fluid-filled cavity, known as the subventricular zone, and a horseshoe shaped area known as the hippocampus. The laboratory of the senior author of the current study, UCSF's Arturo Alvarez-Buylla identified the stem cells in the subventricular zone in 1999 ("Cell", June 11, 1999).

While scientists have known that neural stem cells in the developing brain produce particular types of neurons based on where the stem cells are located in the embryo, studies carried out in cell culture have suggested that adult neural stem cells of the fully formed brain can give rise to many types of brain cells.

In the current study, conducted in mice, the team set out to explore whether neural stem cells in different locations of the subventricular zone are all the same. They did so using a method they developed to follow the fate of early neonatal and adult neural stem cells in 15 different regions of the subventricular zone. These cells typically produce young neurons that migrate to the olfactory bulb, where they mature into several distinct types of interneurons, neurons that are essential for the sense of smell.

To the team's surprise, the adult neural stem cells in the various regions of the subventricular zone each gave rise to only very specific subsets of interneurons. Moreover, the stem cells were not susceptible to being re-specified. When they were taken out of their niche and transplanted into another region of the subventricular zone, they continued to produce the same subset of interneurons. Similarly, they retained their specialized production of distinct subtypes of neurons when removed from the animals' brains and exposed to a cocktail of growth factors in a culture dish.

The findings, says the lead author of the study, Florian T. Merkle a graduate student in the Alvarez-Buylla lab, suggests that while adult neural stem cells of the subventricular zone can produce the three major types of brain cells -- astrocytes, neurons and oligodendrocytes -- when it comes to neurons they seem to be specified, or programmed, to produce very specific subtypes.

"The data supporting the finding is remarkably clean and was highly unexpected," says senior author Alvarez-Buylla, UCSF Heather and Melanie Muss Professor of Neurological Surgery. "We've been studying this region of the brain for many years and Florian's data has produced a different scenario, so we have to readjust now."

"We should abandon the idea that these cells are good for making any kind of neuron. This is just not going to be the case unless we find ways to reprogram these cells genetically."

The insight, says Merkle, is a key step toward understanding the molecular mechanisms of neural stem cell potential. "Now you could compare adult stem cells in different regions at the genetic level. Since different neural stem cells make different types of neurons, maybe you could determine which genes are important for making, say, dopaminergic cells. In theory you could activate these genes in embryonic stem cells in the culture dish to try to create the desired type of neuron".

The Alvarez-Buylla lab has identified neural stem cells in the adult human brain, but it is not known if these cells are heterogeneous. If human brains show a similar regionalization of stem cells, it might also be possible, says Alvarez-Buylla, to harvest them from the brains of patients, expand their numbers in the culture dish to obtain a particular neuron type, and transplant them back into patients.

Notably, the distribution of adult neural stem cells throughout the subventricular zone raises the possibility, he says, that the cells' activity is regionally modulated in order to regulate the production of different types of neurons. "This may provide a mechanism for the brain to dynamically fine tune the olfactory bulb circuitry, raising a fascinating basic question about neuronal replacement: Why are so many different types of neurons, with such diverse origins, required for olfactory function?"

"The implication for cell-based therapies might be that it isn't sufficient to replace one neuron," he says. "You might have to replace combinations of different neuronal types when it comes to reestablishing neural function."

The finding, he says, has not been without its hints. In 1996, the lab reported (PNAS, Dec. 1996) what he describes as "an amazing network of pathways" that collect adult neural stem cells from throughout the wall of the lateral ventricle of the subventricular zone.

"It's taken us 10 years," he says, "to figure out that these pathways reflect the transport of young neurons of different types born in unique locations."

The results of their study are reported online in "Science Express" July 5, and will be published in an upcoming issue of "Science."

The study was funded by the National Institute of Neurological Disorders and Stroke, which is part of the National Institutes of Health, a fellowship from the National Science Foundation and a gift from Francis and John Bowes.