UCSF stem cell study reveals cells' capability in mouse brain tissue
repair
UCSF scientists have determined that adult stem cells in a specific
region of the mouse brain have a built-in mechanism that allows the
cells to participate in the repair and remodeling of damaged tissue
in the region.
As the cells are also present in the human brain, the same capacity
or potential may exist in humans, the researchers say. If they do, it
is possible that the cells' behavior could be enhanced to treat
tissues damaged throughout the brain by disorders such as stroke and
traumatic injury.
The study, reported in the December 15 issue of Cell, was led by Chay
T. Kuo, MD, PhD, a UCSF postdoctoral fellow in the laboratory of
senior investigator Yuh-Nung Jan, PhD.
Kuo is one of 16 UCSF CIRM Stem Cell Scholars – up and coming young
scientists funded by the California Institute for Regeneration
Medicine, established by California voters in 2004 to allocate $3
billion over 10 years to support stem cell research.
"The results were very surprising," says Kuo. "Our results show that
neural stem cells in mice have the ability to sense damage in their
environment that leads to their subsequent proliferation to help
restore local tissue integrity. If we can figure out how this
happens, and determine that it occurs in human neural stem cells, we
may be able to increase the effect and harness it for therapeutic
use."
Understanding this proliferative capacity during environmental change
is critical, he says, as adult neural stem cells in this region may
sometimes proliferate out of control to form brain tumors. This
possibility has been reported and is being explored by scientists in
the UCSF Institute for Regeneration Medicine and UCSF Department of
Neurological Surgery.
The scientists focused their study on postnatal neural stem cells
that lie next to the lining of the brain's lateral ventricles, or
cavity, in a region known as the subventricular zone (SVZ). In 1999,
the lab of study co-author Arturo Alvarez-Buylla, PhD, UCSF Heather
and Melanie Muss Professor of Neurological Surgery, discovered that
cells in this region known as astrocytes function as adult neural
stem cells in mice (Cell, June 11, 1999) and later discovered similar
cells within the human brain (Nature, Feb. 19, 2004). The cells are
recognized as a major source of adult stem cells in the mammalian
brain.
Scientists have known that neural stem cells play a key role in both
embryonic and postnatal mice, driving the development of specialized
cells within the brain such as neurons, astrocytes, oligodendrocytes,
and ependymal cells. And they have identified many of the molecular
pathways that control neural stem cell behavior in embryonic mice.
But relatively little was known about the molecular programs that
control neural stem cells in the postnatal mouse, or how neural stem
cells may respond to tissue damage -- two key questions for
scientists exploring the potential of these cells to treat disease.
To shed light on these issues, Kuo and his colleagues genetically
engineered neural stem cells and ependymal cells in the SVZ of
newborn mice in such a way that they lacked two key proteins, named
Numb and Numblike.
These proteins are known to play a critical role in maintaining
neural stem cell function in embryonic mice, but scientists have not
known their actual function. They suspected that the proteins might
be active in the SVZ of postnatal mice as well. If so, they reasoned,
preventing the proteins' synthesis might inhibit the cells' local
activity and, in so doing, reveal their postnatal function. At the
same time, if the cells' activity was inhibited by the absence of the
proteins, there could be tissue damage in the SVZ, providing a model
for exploring the way in which the neural stem cells responded to it.
The strategy paid off.
Kuo and his colleagues' examination of postnatal mouse brains on
autopsy seven and 14 days after the genetic modification revealed
that absence of proteins Numb and Numblike led to severe brain
ventricle enlargement. This defect resulted from damage of ependymal
cells, which form the epithelial lining of the brain ventricles, and
of neuroblasts, which evolve into neurons. Thus, it was evident that,
as in embryonic mice, the proteins play a crucial role in the
maintenance of cells in the region, and revealed a previously unknown
function for them in assuring ependymal layer integrity.
Wholly unexpected, however, was the fact that damage to the left
ventricular wall was substantially repaired when these sick mice were
examined six weeks later. As a result of a known limitation of the
genetic engineering technique that Kuo employed – some neural stem
cells escaped gene deletion, thus allowing the Numb protein they
synthesized to remain intact – some neural stem cells had continued
to function. Faced with damage in the region, these cells had
responded, mediating the rebuilding of ventricular wall lining and
establishing a modified neural stem cell environment.
The scientists do not know the precise mechanisms by which the stem
cells carried out their response. But it was astonishing, says study
senior investigator Jan, who is , a Howard Hughes Medical Institute
investigator, the Jack and DeLoris Lange Endowed Chair in Molecular
Physiology and professor of physiology and biochemistry at UCSF.
"The holes that had formed in the brain ventricular wall had largely
been repaired. These adolescent mice looked quite good. The finding
shows that the brain has the ability to repair itself and that it is
more plastic than previously appreciated.
The model Kuo devised, says Jan, will provide a powerful tool for
studying the response of neural stem cells of the SVZ to damage
caused by such conditions as stroke and trauma.
It can also be used to test the impact of deleting various genes from
neural stem cells of the SVZ. The results, he says, would contribute
to scientists' understanding of the full pathway of genes needed to
prompt differentiation of neural stem cells both in the brain and in
the culture dish. In this sense, he says, "the deletion of Numb and
Numblike was a test case."
In collaboration with other UCSF neuroscientists, as well as
neurosurgeons, Kuo is currently exploring whether neural stem cells
of the SVZ can respond to damage outside the ventricle region and, if
so, whether inflammation in the traumatized area prevents the stem
cells from restoring the tissue.
And he wonders whether the epilepsy that can occur in stroke and
trauma patients, often years after the injury, results from
unsuccessful attempts by the progeny of neural stem cells to make
synaptic connections with other cells in the damaged region.
Numerous other UCSF labs are also investigating neural stem cells in
the SVZ of the embryonic and postnatal brain, with an eye toward
developing therapies for Parkinson's, epilepsy and ALS, says Arnold
Kriegstein, MD, PhD, the John G. Bowes Endowed Chair in Stem Cell and
Tissue Biology and director of the UCSF Institute for Regeneration
Medicine.
And like the neural stem cells they study, these scientists are
collaborating, making connections aimed at building new material. "As
such," says Kriegstein, "their work demonstrates the power of
synergy."
###
Other co-authors of the study were Zaman Mirzadeh and Denan Wang of
UCSF, Mario Soriano-Navarro and Jose Garcia-Verdugo of Unidad
Asociada Centro de Investigatcion Princepe Felipe-Universidad de
Valencia, Mladen Rasin and Nenad Sestan of Yale University School of
Medicine, and Jie Shen of Harvard Medical School.
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.
Related links:
http://pub.ucsf.
UCSF finding advances insight into adult stem cells in human brain
http://pub.ucsf.
UCSF receives CIRM stem cell training grant
http://stemcellfact
UCSF Institute for Regeneration Medicine
Public release date: 14-Dec-2006
Contact: Jennifer O'Brien
jobrien@pubaff.
415-476-2557
University of California - San Francisco
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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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