FYI
This is from a website called "Medical Tribune" --
Cloning May Yield Supply Of Dopamine-Producing
Neurons
Research raises new questions about pathogenesis of
the movement disorder
Charles Bankhead
One laboratory's search for sources of
dopamine-producing cells has raised the intriguing
possibility that Parkinson's disease might arise
from the loss of neuronal progenitor cells,
rather than a loss of dopamine neurons.
"It's a far-out concept, but we really need to ask
the question, now that we know these
[progenitor cells] are present in the brain," Paul
M. Carvey, Ph.D., chairman of
pharmacology at the Rush Medical College in Chicago,
told Medical Tribune. "Perhaps
Parkinson's occurs when the brain no longer has the
capability to replenish these cells. The
idea seems pretty far out, but keep in mind that
seven or eight years ago, we didn't think
progenitor cells existed in the brain."
The question emerged from work on fetal rate
mesencephalic progenitor cells as potential
sources of dopaminergic neurons. The Chicago
research team had previously reported their
ability to use cytokines to transform progenitor
cells into dopaminergic neurons. Using fetal
tissue to acquire transplantable dopamine neurons
raises scientific, logistical and ethical
issues, Dr. Carvey said, explaining his team's
decision to investigate alternative sources of
dopamine-producing cells.
The Chicago physician and his colleagues reported on
their successful expansion of rodent
progenitor cell colonies into dopamine-producing
neurons at the recent International
Congress on Parkinson's Disease sponsored by the
Pacific Parkinson's Research Institute in
Vancouver.
"There is a big controversy as to what to call these
cells," Dr. Carvey said. "I think they can
best be described within the context of stem cells.
There are stem cells, which are
omnipotent cells that are organ specific. There are
embryonic stem cells, which are
omnipotent but are not organ specific. Then there
are progenitor cells, which could be
considered as pleuripotent and capable of
formulating only specific types of cells."
"We've gone into the primordia of the mesencephalon
to obtain cells that we felt required
only one or two more signals to make a dopamine
neuron," he explained. "We have been able
to get these cells to perpetuate themselves in
culture, just like stem cells. We have played
around with mechanisms for getting them to convert
to a specific phenotype, and we have
been able to do that, too."
Phenotypic conversion has been accomplished by the
use of cytokines, specifically
interleukin-1 (IL-1), IL-11, leukemia inhibitor
factor, and glial cell line-derived neurotrophic
factor.
"Several years ago, we began studying cytokines and
how they might affect the development
of the hematopoietic blood system," Dr. Carvey said.
"Normally, you don't think about
cytokines in the brain, except as they relate to
infection. We felt that nature might use a
similar signaling system to control differentiation
in the brain.
"Specifically, we studied cytokines to see whether
they affect phenotypic development in the
brain," Dr. Carvey added. "In this case, it turns
out that they do." The obser-vation of
cytokines' ability to influence phenotypic
development could open an entirely new field of
cytokine investiga-tion, aside from inflammatory
processes, he noted.
After demonstrating the ability of cytokines to
convert progenitor cells into dopamine
neurons, Dr. Carvey and his associates evaluated the
potential for expansion of a clonal
population from a single cell.
In their presentation at the Parkinson's Congress,
they reported that a majority of clones
stained positive for the dopamine neuron marker
tyrosine hydroxylase (TH).
Conversion to TH cells varied from a small number of
cells to 50 percent, according to Dr.
Carvey. Some clones exhibited no conversion.
The ability to clone progenitor cells and produce a
high yield of dopamine-producing
neurons "would not only provide an unlimited,
on-demand source of cells for grafting, but the
opportunity to transfect them with genes that would
enhance their utility in the treatment of
Parkinson's disease," Dr. Carvey said.
The work with progenitor cells "opens our
perspective on how we think the brain might
change its cytoarchitecture," he added.
While animal tissue offers the potential of an
unlimited source of transplantable cells,
problems associated with tissue rejection introduce
a new variable to an already variable
clinical situation, as reflected in studies of pig
cells transplanted into humans, according to
Curt Freed, M.D., who helped pioneer transplantation
of human fetal cells into Parkinson's
patients.
"The variability of outcome is something we really
need to understand better," said Dr.
Freed, who is director of the neuroscience program
at the University of Colorado in Denver.
"Parkinson's is probably variable as a disease in
the individual. Additionally, transplantation
is variable in terms of how well the cells survive
and grow. Even if the cells grow, we don't
know whether the transplant will overcome the defect
in the brain."
"Animal cells will have the same varia-bility," he
added. "In addition, use of animal cells
introduces a huge variable in the form of immune
response. So far, the immune barrier has not
been solved. With our transplants [using human
tissue], no patient receives
immunosuppressant drugs. With animal tissue, you
have to be quite aggressive with
immunosuppression."
--
Charlotte A. Mancuso
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