June 6, 2003 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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