Promise Of Stem Cells Amplified; New Evidence Shows Cells May Help
Treat Many Disorders Including Paralysis And Brain Cancer
Continuing to counter the dogma that once brain cells give out,
they're gone forever, new evidence shows that newly created neurons
may provide hope for treating a wide variety of disorders.

2004-11-01

Embryonic stem cells have been shown to restore movement after
paralysis. And with genetic engineering, stem cells can act as
sophisticated protein delivery systems. Scientists have used them to
deliver GDNF, a factor to aid in the survival of neurons targeted by
Parkinson's and Huntington's diseases. Another team has used them to
seek and destroy brain tumor cells. And a Norwegian group has proved
that even in adults, neural stem cells have the power to become
functioning neurons.

Scientists at the University of California , Irvine , have reversed
spinal cord damage in paralyzed adult rats, allowing them to walk
again. The researchers, led by Hans Keirstead, PhD, used human
embryonic stem cells, which have the potential to become any cell
type in the entire body—and turned them into oligodendrocytes—a type
of cell in the brain. Oligodendrocytes form the fatty substance
myelin that insulates the long wirelike extensions of nerve cells,
called axons. Oligodendrocytes wrap themselves around these axons,
allowing electrical signals to be rapidly transmitted to other cells
in the brain and body.

Spinal cord injury results in a cut through the axons, breaking the
information circuit and resulting in paralysis. Even if the neurons
are able to regrow new axons, they require oligodendrocytes to form
new myelin. “By transplanting new oligodendrocytes, we repaired the
lost insulation,” Keirstead says.

The researchers manipulated human embryonic stem cells to become
oligodendrocyte progenitor cells (OPCs), an intermediate step before
becoming oligodendrocytes. Once implanted to the nervous system of
rats, the cells completed their maturation.

When the OPCs were transplanted into rats just seven days after a
spinal cord injury, the rats regained the ability to walk nine weeks
later. Rats that had to wait until ten weeks after injury, however,
did not improve with the transplant. Keirstead says that scar-forming
cells may block the re-insulation of axons by the oligodendrocytes.
“Older, scarred spinal cord injuries pose another hurdle that we have
yet to conquer,” he says. “Future studies may find a way around this
barrier.”

The broader accomplishment of this work, says Keirstead, is the
generation of a highly pure population of oligodendrocytes from human
embryonic stem cells. Previous efforts to collect oligodendrocytes
from human fetuses resulted in samples contaminated with other cell
types and oligodendrocytes at different stages of development. This
pure population will allow researchers to explore the value of using
oligodendrocytes in other applications.

In other work, scientists at the University of Wisconsin at Madison
have rescued the cells that are attacked by Parkinson's disease and
Huntington's disease. Both diseases are movement disorders that
specifically kill off neurons that use the neurotransmitter dopamine.
“Replacement of dopamine neurons using embryonic stem cells has long
been the holy grail,” says Clive N. Svendsen, PhD. “But stem cell
transplantation can introduce serious problems, including tumors and
dyskinesia, or impaired, sporadic muscle movements.”

So instead of replacing the dopamine cells, she and her colleagues
found a way to provide support to neurons under attack. Dopamine
neurons require glial-derived neurotrophic factor (GDNF) to survive.
So even if stem cells could be successfully introduced to an adult
brain, chances are they would require GDNF. Yet in an earlier study,
Berhstock's group showed that GDNF alone could restore function to
the neurons affected by Parkinson's.

In this earlier study, the researchers delivered GDNF to the brains
of patients using a pump and a small catheter implanted in the
putamen, a brain area severely stricken by Parkinson's disease. But
because the delivery system was so localized, the GDNF did not travel
very far. Nevertheless, the patients' symptoms and dopamine neurons
improved.

“We thought real cells might better deliver GDNF to the brain,”
Svendsen says. The group considered using embryonic stem cells, but
realized they might lead to tumors and dyskinesia, so they tried
neural stem cells. These cells don't have quite the enormous
potential of embryonic stem cells, but they can become astrocytes, a
type of glial cell found in the brain. Best of all, they do not
induce tumors.

“We wanted to use genetically modified stem cells as organic GDNF
‘mini-pumps,'” says Svendsen. In order to get the astrocytes to
produce and deliver GDNF, they gave them a gene for the growth factor
and another gene that acts as an “on/off switch” for GDNF production.
The researchers were able to control the release of GDNF with the
antibiotic doxycycline. They lowered GDNF production simply by
administering the drug to the animals, and then resumed GDNF
production by withdrawing it.

They then transplanted the genetically modified astrocytes into the
brains of rats that served as animal models of either Parkinson's
disease or Huntington's disease. The GDNF produced by these
astrocytes caused the dopamine neurons to sprout new fibers and to
transport the GDNF back to the neuron cell bodies, signs of improved
neuronal health and function. “The study provides evidence that this
delivery method might be used as a clinical tool for Parkinson's and
Huntington's diseases,” says Svendsen.

Another group of scientists has used the remarkable ability of human
neural stem cells to home in on harmful brain tumors. Evan Snyder,
MD, PhD, of the Burnham Institute in San Diego, and his colleagues at
Yonsei University in South Korea implanted neural stem cells to adult
mice and watched as they attacked the brain tumors.

Cancerous tumors move quickly throughout the brain. “Brain tumors are
entirely untreatable because they are so migratory,” says Snyder.
“They are inevitably lethal because they can evade even the most
extensive surgical excision and therapies. Neural stem cells are
uniquely poised to treat tumors because the cells are attracted to
areas of abnormality.”

The researchers used genetic engineering to turn the cells into
delivery vehicles for therapeutic agents. They inserted the gene for
tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This
substance, secreted by the implanted stem cells, is like kryptonite
to the hazardous tumor cells.

The scientists studied the most lethal type of brain cancer:
intracranial glioblastomas. Adult mice with the tumors received
transplants of the stem cells that could deliver TRAIL. The stem
cells traveled throughout the main tumor site and even to the
cancer's satellite locations, called metastases. The stem cells
attacked the cancer and reduced tumor size dramatically.

“Treating brain tumors is perhaps the most promising use of stem
cells,” Synder says. “It's truly the ‘low-hanging fruit' in the
field.”

In other research, scientists at Oslo 's University Hospital have now
shown that even adults harbor stem cells that can become real
neurons. Throughout our lives, neural stem cells are born in the
ventricular zone, the areas inside hollowed-out spaces in the brain
that contain cerebrospinal fluid. Several groups of researchers have
watched these cells mature into what look like neurons. But the true
test of a neuron's function—electrical conductivity—had not yet been
seen.

Iver Langmoen, MD, and his colleagues harvested the adult neural stem
cells from the ventricular zone of patients undergoing brain surgery.
In the laboratory, the stem cells formed aggregates called
neurospheres, which must be dissociated before subsequent divisions
can occur. After several generations, the researchers treated the
cells with a mix of nutrients to help them differentiate into
neurons.

They used a tiny electrode designed to measure the electrical
activity of individual neurons. This technique, called patch-clamp
electrophysiology, revealed that the cells indeed fired action
potentials, a neuron's electrical signature. The cells also release
glutamate, one of the brain's most important neurotransmitters. In
addition, the neurons expressed glutamate receptors, indicating that
they could sense glutamatergic messages in addition to sending them.

Final evidence that the cells were able to communicate as neurons
came from experiments in which the researchers recorded electrical
activity from pairs of neighboring neuronlike cells simultaneously.
This cemented the notion that the cells used a classical neuronal
mechanism of transmission.

“Stem cells from the adult human brain can develop into functional
neurons and establish networks,” says Langmoen. The researchers hope
to explore the possibility of autotransplantation, in which neural
stem cells gathered from the brain of a patient could be multiplied
in the lab and then returned to that person's brain. “Such a scenario
would avoid the ethical and immunological complications associated
with embryonic stem cell therapy,” Langmoen says.

Editor's Note: The original news release can be found here
http://apu.sfn.org/content/AboutSFN1/NewsReleases/am2004_human.html

This story has been adapted from a news release issued by Society For
Neuroscience.

SOURCE: Science Daily (press release)
http://tinyurl.com/4e2mx

* * *Murray Charters <[log in to unmask]>
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