Source: Jennifer O'Brien
jobrien@pubaff.
415-476-2557
05 July 2007
UCSF's Arturo Alvarez-Buylla
Insight into neural stem cells has implications for designing
therapies
Scientists have discovered that adult neural stem cells, which exist
in the brain throughout life, are not a single, homogeneous group.
Instead, they are a diverse group of cells, each capable of giving
rise to specific types of neurons. The finding, the team says,
significantly shifts the perspective on how these cells could be used
to develop cell-based brain therapies.
The results of their study are reported online in "Science Express"
today, July 5, and will be published in an upcoming issue
of "Science."
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 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.
UCSF is a leading university that advances health worldwide by
conducting advanced biomedical research, educating graduate students
in the life sciences and health professions, and providing complex
patient care.
Alvarez-Buylla lab:
http://neurosurgery
rez_buylla_lab.
UCSF Institute for Regeneration Medicine: http://irm.ucsf.
http://pub.ucsf.
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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