Reprogrammed Stem Cells Work on Parkinson's
April 8, 2008
A study in rodents suggests that skin cells can be transformed into
neurons to treat neurodegeneration.
By Courtney Humphries
When researchers announced two years ago that they had found a way to
turn ordinary skin cells into stem cells, it opened up the
possibility that stem cell therapies might sidestep the logistical
and ethical hurdles of obtaining stem cells from embryos.
These "reprogrammed" stem cells seem to have the ability to transform
into any kind of cell, a property known as pluripotency. But the
concept has also met with skepticism about the abilities and
potential dangers of the cells. A new study in the Proceedings of the
National Academy of Sciences by scientists at MIT and Harvard shows
that reprogrammed cells, also called induced pluripotent stem (iPS)
cells, can become functioning neurons when transplanted into the
brains of mice and rats; the researchers also showed that the cells
can improve symptoms in a rat model of Parkinson's disease.
The research team, led by Rudolph Jaenisch at the Whitehead Institute
for Biomedical Research at MIT, used the previously developed method
for reprogramming cells, in which skin cells of a mouse can be made
pluripotent when infected with a retrovirus carrying four genes.
First, the scientists showed that they could turn mouse skin cells
into functioning neurons in culture. They then transplanted these
neurons into the brains of mice while they were still fetuses. After
the mice grew into early adulthood, the researchers examined the
brains and identified the transplanted cells, which had been labeled
with a fluorescent marker. The cells "migrate nicely into the brain
and mature in the brain," says Marius Wernig, a postdoctoral fellow
at the Whitehead Institute. "They adopt functions of mature neurons."
Next, the group tested whether these functioning neurons could repair
a defect in an animal model of disease. Parkinson's involves a loss
of a specific population of neurons----those that produce dopamine.
The study used a model for Parkinson's in which rats are given a
toxin that kills dopamine neurons on one side of the brain. Although
the animals appear normal, when their dopamine neurons are stimulated
with amphetamine, they begin to turn in circles in the direction of
the damaged side. In rats that were given transplants of neurons
derived from iPS cells, the motor defect improved.
John Gearhart, a stem cell biologist at Johns Hopkins School of
Medicine who was not involved in the study, says that previous
studies with the reprogrammed cells have had conflicting results--
some studies show that the cells have similar abilities as embryonic
stem cells, while others don't. "This is an important study," says
Gearhart, because it compares the iPS cells with neurons derived from
embryonic stem cells.
It is not known exactly how boosting the expression of just four
genes manages to induce such a powerful state. Two of the genes are
known oncogenes, or tumor promoters, that help cells proliferate; the
other two are involved in maintaining the pluripotency of stem cells.
Although the study provides a proof of concept, much has to be done
before the reprogrammed stem cells could be used in the clinic. At
present, they are considered unsafe for use in humans because the way
they are engineered has the potential to cause cancer. Wernig says
that the next major effort is "to try to reprogram human cells
without the use of a retrovirus and without oncogenes," perhaps by
targeting the genes with drugs.
For many years, a small group of patients with Parkinson's disease
have received experimental cell transplants using dopamine neurons
derived from fetuses. But the use of fetal tissue poses ethical and
logistical hurdles for widespread use. Scientists have performed
similar experiments in animals using stem cells derived from embryos
or created with nuclear transfer, also known as therapeutic cloning.
But iPS cells offer a way to avoid the use of embryos as well as the
technical challenges of nuclear transfer. And if the cells came from
a patient's own skin, there would be no potential complications from
immune rejection of foreign tissue.
When the team first performed the experiment, many rats developed
tumors, which seemed to arise from the fact that not all of the iPS
cells had fully transformed into neurons when they were transplanted.
Tumors such as these have also been observed in experiments with
embryonic stem cells. In this study, however, the researchers
performed another set of transplants, first using a cell-sorting
method that can identify and remove any cells that have failed to
differentiate. "When we eliminated the undifferentiated cells from
mixture, we got very clean transplants,
neurologist at Harvard Medical School who collaborated on the
transplant experiments. The rats given these purified cells did not
go on to develop tumors. He believes that the varying purity of
transplants may prove to be a key factor in why some of the fetal
cell transplants have not succeeded as well as others.
http://www.technolo
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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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