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"Immortalized" Cells Enable Researchers to Grow Human Arteries

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Duke Health News 919-660-1306

DURHAM, N.C. -- In a combination of bioengineering and
cancer research, a team of Duke University Medical Center
researchers has made the first arteries from non-embryonic
tissues in the laboratory, an important step toward growing
human arteries outside of the body for use in coronary artery
bypass surgery.

In 1999, Duke researchers led by Laura Niklason, M.D.,
reported in the journal Science on experiments in which they
grew pig arteries in a novel "bioreactor" system that mimics
the fetal environment, and then successfully implanted these
bioengineered arteries back into the pig. Unfortunately,
researchers found that human artery cells did not possess
enough life cycles to be grown into functional arteries.

The key to overcoming this hurdle was found in a cancer
research lab. Every time a cell divides, the ends of its
chromosomes, or telomeres, erode until they become so short
that the cell receives a signal to stop growing. While at the
Massachusetts Institute of Technology, current Duke researcher
Chris Counter, Ph.D., had previously cloned the hTERT (human
telomerase reverse transcriptase subunit) component of the
enzyme telomerase that stops telomeres from shortening, and had
shown that expression of hTERT permitted some human cells to
continue to divide indefinitely, in effect making them
immortal.

Working with Niklason and Counter, then medical student Andy
McKee found that when the hTERT gene was introduced into smooth
muscle cells, key components of an artery, the life span of the
cells were extended long enough to form arteries in the
laboratory.

The results of the Duke experiments were published today
(June 6, 2003) in EMBO Reports, the journal of the European
Molecular Biology Organization.

"After introducing the human cells with hTERT, we found that
the resulting cells not only proliferated long beyond their
normal lifespan, but retained characteristics of normal smooth
muscle cells," Niklason explained. "Furthermore, using these
smooth muscle cells, we were able to engineer mechanically
robust human arteries, a crucial step toward creating arteries
for bypass patients."

This is the first time arteries have been grown from
non-neonatal vascular cells, the researchers said. This
achievement is important, they continued, since the goal is to
engineer arteries that will resist immunological attack, so
they must be grown from cells taken from the actual patients
who will ultimately receive the arteries.

To create the arteries, the researchers fashioned a tube
from a thin sheet of a biodegradable polymer, which, like a
sponge, is 97 percent air. The treated smooth muscle cells were
then impregnated throughout the polymer tube. The bioreactor
pulsed a vitamin and nutrient solution through and around the
tube, approximating as closely as possible the conditions that
would exist in nature.

Once the smooth muscle cells proliferated and filled all the
spaces within the dissolving polymer scaffolding, the
researchers added endothelial cells, which line the interior of
blood vessels, to complete the artery.

"We view the results of this study as the proof-of-principle
that this approach will ultimately lead to tissues that can be
used in humans," Niklason said.

According to Counter, the hTERT component of telomerase was
first cloned in 1997, and researchers in the areas of cancer
and bioengineering are slowly turning their attention to
potential new avenues to exploit the properties of
telomeres.

"Telomeres are present in all normal dividing cells and act
as a built-in check against unwanted cellular proliferation,"
Counter explained. "In this case, telomere shortening worked
against us, preventing the cells from dividing long enough to
form an artery in the laboratory. So we stole a trick cancer
cells use to keep dividing; namely we turned on hTERT to stop
telomerase shortening."

The researchers did not detect any signs of unwanted
cellular proliferation in their bioengineered arteries,
although Counter did emphasize that before these arteries can
be implanted into humans, the researchers must ?turn off?
hTERT. It is expected that the implanted arteries would then
"age" as would native arteries.

Niklason estimates that it could take up to 10 years before
these bioengineered arteries will be routinely implanted in
patients with heart disease. Currently, it takes about 12 to 13
weeks to grow an artery strong enough to withstand the blood
pressures experienced in humans, so she is exploring new
approaches that will create stronger arteries faster. Also, it
is still not known how the arteries would react once inside the
body.

It is estimated that about 100,000 out of 1.4 million
Americans who need small vessel grafts are unable to get them
because their own or prosthetic vessels are unsuitable. While
polymer vessels can be used when large vessels are required,
the smaller ones tend to become clogged with clots.

The research was supported by the American Foundation for
Aging Research and the National Cancer Institute.

Other members of the Duke teams were S.R. Banik, Ph.D.,
Matthew Boyer, Nesrin Hamad, Ph.D., and Jeffrey Lawson,
M.D.

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