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By Repairing Vessels, Bone Marrow Cells Slow Atherosclerosis in Mice

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Duke Health News 919-660-1306

CHICAGO, IL -- Duke University Medical Center researchers
have shown that an age-related loss of specific stem cells that
continually repair damage to blood vessels is critical to
determining the onset and progression of atherosclerosis. Stem
cells are immature cells that have the potential to mature into
a variety of different cells.

This novel view of the disease, based on experiments in
mice, constitutes a potential new avenue in the treatment of
one of the leading causes of death and illness in the U.S., the
researchers said.

It could ultimately be possible, they continued, to inject
these stem cells into patients, or to induce the patient?s own
stem cells to differentiate into progenitor cells capable of
arterial repair, to forestall or even prevent the development
of atherosclerosis, a disease process that causes arteries to
clog and become less elastic. When atherosclerosis affects
arteries supplying the heart with oxygen and nutrients, it
causes coronary artery disease and puts patients at a much
higher risk for a heart attack.

"We believe that the arteries of young people are remarkably
resistant to damage because stem cells known as vascular
progenitor cells (VPCs) produced in the bone marrow are
continually repairing damage caused to the vessels," said
Frederick Rauscher, a fourth-year medical student at the Duke
University School of Medicine who presented the results of the
Duke today (Nov. 19, 2002) at the 75th annual scientific
session of the American Heart Association.

"As we age, it appears that we exhaust or deplete our store
of VPCs, which means that damage to vessels cannot be
repaired," Rauscher continued. "This idea that stem cells can
rejuvenate vessels could explain one of the biggest questions
in our understanding of atherosclerosis -- why does it appear
to be a disorder seen almost exclusively in older people?"

Rauscher's presentation is one of five finalists for the
Louis N. and Arnold M. Katz Basic Research Prize for Young
Investigators.

Arteries can be damaged over time by the collective effects
of high cholesterol, high blood pressure, diabetes, smoking and
even infection. The researchers believe that VPCs can help
offset these risk factors by rejuvenating the vessels.

"These findings are very important," said Pascal
Goldschmidt, M.D., senior member of the research team and chief
of cardiology at Duke. "For a long time we've known that aging
is an important risk factor for coronary artery disease, and
we've also known that these diseases can be triggered by
smoking, bad diet, diabetes, high blood pressure and other
factors.

"But if you compare someone who is over 60 with someone who
is 20 with the same risk factors, there is obviously something
else going on as well," Goldschmidt continued. "The possibility
that stem cells may be involved is a completely new piece of
the puzzle that had not been anticipated or appreciated
before."

In their experiments, the Duke team used mice specially bred
to develop severe atherosclerosis and high cholesterol levels.
The researchers injected VPCs from normal mice into these
atherosclerosis-prone mice numerous times during a 14-week
period. As a control, an equal of number of the same kind of
atherosclerosis-prone mice went untreated.

"After 14 weeks, the mice treated with the stem cells had a
significantly reduced number of lesions in the aorta, despite
no differences in cholesterol levels," Rauscher said.

Specifically, the researchers detected a 69 percent decrease
in the number of lesions in the aorta, the main artery of the
heart, and a 42 percent decrease in lesions where the aorta
meets the heart.

Using specific staining techniques on the aortas, the
researchers were able to determine that the donor stem cells
?homed in? on areas where atherosclerotic lesions are most
common, especially where smaller vessels branch off from larger
vessels. These areas tend to experience "turbulence" or
"eddying" of blood.

"We then looked at the vessels under a microscope, it
appeared that the stem cells not only went where they were
needed most, but that they differentiated into the proper cell
types," Rauscher said. "Some turned into endothelial cells
lining the artery, while others turned into the smooth muscle
cells beneath the endothelium that help move blood through the
arteries."

To further prove that the donor stem cells were responsible
for rejuvenating arteries, the scientists measured the lengths
of structures at the end of chromosomes known as telomeres of
the endothelial cells and found that they were longer in the
treated mice than the untreated mice. Over time, telomeres are
known to shorten as the organism ages.

"These experiments support the new concept that the loss of
a suitable source of VPCs contributes to the development of
atherosclerosis," Rauscher said. "Whereas traditionally we have
focused on removing multiple sources of vascular injury, we now
demonstrate that an alternative approach, vascular
rejuvenation, can positively impact the development of
atherosclerosis in the continued presence of vascular
injury."

While the direct use of stem cells as a treatment may be
many years off, the researchers said, it is likely that
strategies currently used to reduce the risks for heart disease
-- such as lifestyle modifications and/or different medications
-- preserve the collection of these rejuvenating stem cells for
a longer period of time, which delays the onset of
atherosclerosis.

For Goldschmidt, a major question is whether researchers can
somehow use these cells for patients who already have a
lifetime of atherosclerosis.

"We need to look at the possibility of re-training stem
cells that would otherwise be targeted to a different organ
system to help repair the cardiovascular system," he said.
"Another interesting question is whether rheumatoid arthritis,
as an example for chronic inflammatory disorders, causes stem
cell loss, since such arthritis is a risk factor for coronary
artery disease. The chronic process of joint disease could
consume stem cells that could otherwise be used for the repair
of the cardiovascular system. We are just beginning to
appreciate the links between stem cells and cardiovascular
disease."

Rauscher is supported by a fellowship from the Stanley
Sarnoff Endowment for Cardiovascular Science.

Other members of the Duke team include: Bryce Davis, Priya
Ramaswami, Anne Pippen, David Gregg, Brian Annex, M.D.,
Chunming Dong, M.D., Tao Wang, Ph.D., and Doris Taylor,
Ph.D.

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