AURORA, Colo., Sept. 22 (AScribe Newswire) -- Researchers
at the University of Colorado Denver School of Medicine say
manipulating embryo-derived stem cell precursors prior to
transplanting them holds the key to using stem cell
technologies for repairing spinal cord injuries in humans.
In the online Journal of Biology, Dr. Stephen Davies, an
associate professor of neurosurgery reports his research
team has produced two types of spinal cord support cells
called astrocytes ("star" cells) from the same
embryo-derived stem cell-like cells called Glial Restricted
Precursor cells (GRPs) that have remarkable effects on the
injured spinal cord.
Astrocytes carry out many important functions within the
brain and spinal cord and account for roughly 70 percent of
the total cells in the Central Nervous System. "To our
knowledge, this is the first time that two distinct
sub-types of Astrocyte support cells generated from a common
stem cell-like precursor cell have been shown to have
robustly different effects when transplanted into the
injured adult nervous system," Davies explains.
When nerve fibers are injured in the adult spinal cord,
their severed ends fail to regenerate and re-connect with
nervous system circuits beyond the injury site.
Inflammation at sites of injury not only promotes the
formation of scar tissue that inhibits the re-growth of
nerve fibers but is also thought to play a major role in the
onset of Neuropathic Pain syndromes that are a common side
effect of severe and even relatively mild spinal cord
injuries. These pain syndromes can be so severe that the
touch of a finger feels like the stab of a knife.
In the embryonic spinal cord however injured nerve fibers
are able to regenerate past sites of injury and reform
Functional connections. It is widely believed that early
astrocytes within the embryonic spinal cord help support
this Regeneration. As the embryonic spinal cord does not
form a scar or develop pain syndromes after injury, Davies
and co-workers hoped therefore that embryonic GRP-derived
astrocytes (GDAs) would confer the striking repair
capabilities of the embryonic spinal cord on the injured
adult spinal cord.
Using signal molecules that are known to be involved in the
generation of embryonic astrocytes during spinal cord
development, Davies and co-workers were able to make pure
cultures of two different types of astrocytes from the stem
cell-like GRP cells.
One type of astrocyte - GDAsBMP - so called because they are
derived from glial restricted precursor cells treated with
bone morphogenetic protein, are remarkably effective at
promoting nerve regeneration and functional recovery. Adult
spinal cord injured rats treated with these cells showed ~40
percent nerve fiber regeneration in just 8 days and had
returned to pre- injury scores in a test of coordinated limb
movement by two weeks after treatment. In addition the
GDAsBMP were also able to protect injured neurons in the
brain from undergoing Atrophy.
The other type of astrocyte cell generated by Davies and
co-workers by treating GRP cells with ciliary neurotrophic
factor -GDAsCNTF - however not only failed to promote nerve
fiber regeneration or functional recovery but also caused
neuropathic pain, a severe side effect that was not seen in
rats treated with GDAsBMP. When the research team
transplanted na?ve GRP cells into adult spinal cord injuries
in rats without first instructing them to turn into GDAsBMP,
the GRP cells also turned in astrocytes that promoted
neuropathic pain.
"Controlling the development of embryonic stem cells
immediately before transplanting them into injured spinal
cords is essential," says Davies, "because doctors cannot
rely on the injured tissues of the body to create the right
types of cells from 'na?ve' embryonic stem cells."
"In order to use stem cell technologies like GRP cells for
repairing the injured spinal cord, scientists and physicians
(and not the injured spinal cord) must control what the GRP
cells turn into" Davies commented. "By giving the GRP cells
the right signal molecules such as BMPs, we have been able
to make desirable cells such as GDAsBMP, rather than
allowing the injured spinal cord to turn the transplanted
GRP cells into highly undesirable cells such as GDAsCNTF.
When we analyzed scar tissue in untreated spinal cord
injuries we found adult astrocytes that closely resemble
GDAsCNTF that promote pain and no recovery."
Davies' and his team, including his wife, Jeannette Davies,
an assistant professor of neurosurgery at UC Denver,
consider the distinction between GDAsBMP and GDAsCNTF a
breakthrough that can change the way stem cell technologies
are used to repair spinal cord injuries.
"Our study shows that different types of immature astrocytes
can have opposite effects on the injured spinal cord and
that not all cells that can be made by na?ve embryo derived
stem cells are necessarily beneficial for repairing the
injured spinal cord," Davies says. "It has long been a
concern that therapies that promote growth of nerve fibers
in the injured spinal cord would also cause sprouting of
pain circuits. However by using GDAsBMP to repair spinal
cord injuries we can have all the gains without the pain."
To that end, Davies and his collaborators, Drs Margot
Mayer-Proschel and Christoph Proschel at University of
Rochester, NY, are developing a safe, efficient and
cost-effective way to make human GDAsBMP with an eye toward
testing this new cell replacement technology in humans. The
eventual result of all his research, Davies hopes, will be a
fast, relatively pain-free spinal cord recovery process that
paves the way for victims of paralysis to recover the use of
their bodies.
This research was supported by the National Institute for
Neurological Disorders and Stroke, the New York State
Department of Health Spinal Injury Research Program, the New
York State Center of Research Excellence for Spinal Cord
Injury and seed funding provided by the Christopher and Dana
Reeve Foundation.
The School of Medicine (http://www.uchsc.edu/som/)
faculty work to advance science and improve care as the
physicians, educators and scientists at University of
Colorado Hospital, The Children's Hospital, Denver Health,
National Jewish Medical and Research Center, and the Denver
Veterans Affairs Medical Center. Degrees offered by the UC
Denver School of Medicine include doctor of medicine, doctor
of Physical Therapy, and masters of physician assistant
studies. The School is part of the University of Colorado
Denver (http://www.ucdhsc.edu/), one of three universities
in the University of Colorado system. For additional news
and information, please visit the UC Denver newsroom
(http://www.uchsc.edu/news/) online.
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CONTACT: Jim Spencer, 303-315-0554, 720-346-4242
