Age-Related Stem Cell Loss Prevents Artery Repair And Leads To Atherosclerosis
Aging has long been recognized as the worst risk factor for chronic ailments like atherosclerosis, which clogs arteries and leads to heart attacks and stroke. Yet, the mechanism by which aging promotes the clogging of arteries has remained an enigma.
Scientists at Duke University Medical Center have discovered that a major problem with aging is an unexpected failure of the bone marrow to produce progenitor cells that are needed to repair and rejuvenate arteries exposed to such environmental risks as smoking or caloric abuse.
The researchers demonstrated that an age-related loss of particular stem cells that continually repair blood vessel damage is critical to determining the onset and progression of atherosclerosis, which 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.
The researchers' novel view of atherosclerosis, 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., they said. Just as importantly, they continued, this loss of rejuvenating cells could be implicated in a broad range of age-related disorders, ranging from rheumatoid arthritis to chronic liver disease.
The results of the Duke research were posted early (July 14, 2003) on the website of the journal Circulation, (http://circ.ahajournals.org). The study will appear in the July 29, 2003, issue of the journal.
At issue is the role of stem cells, which are immature cells produced in the bone marrow that have the potential to mature into a variety of different cells. The Duke team examined specific stem cells known as "bone-marrow-derived vascular progenitor cells" (VPCs).
The researchers believe that it might ultimately be possible to forestall or even prevent the development of atherosclerosis by injecting these cells into patients, or to induce the patient's own stem cells to differentiate into progenitor cells capable of arterial repair.
"Our studies indicate that the inability of bone marrow to produce progenitor cells which repair and rejuvenate the lining of the arteries drives the process of atherosclerosis and the formation of plaques in the arteries," said Duke cardiologist Pascal Goldschmidt, M.D., chairman of the Department of Medicine. "For a long time we've known that aging is an important risk factor for coronary artery disease, and we've also known that this disease 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," he 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. These findings could be the clue to help us explain why atherosclerosis complications like heart attacks and strokes are almost exclusively diseases of older people."
Doris Taylor, Ph.D. a senior member of the research team, sees these findings leading researchers into new areas of investigation.
"For the first time we are beginning to an insight into how aging and heart disease fit together, we've know they go hand-in-hand, but we haven't understood why," she said. "Understanding that we either run out of progenitor cells or that they don't work as well is a big molecular clue to what might be going on in the whole aging process.
"We are excited that as we unravel the mechanisms of this process, we will be able to look deeper into heart and vascular disease, as well as other disease," she added. "These studies form the basis of future collaborations."
In their experiments, the Duke team used mice specially bred to develop severe atherosclerosis and high cholesterol levels. The researchers injected bone marrow cells from normal mice into these atherosclerosis-prone mice numerous times over 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 bone marrow cells had significantly fewer lesions in the aorta, despite no differences in cholesterol levels. Specifically, the researchers detected a 40-60 percent decrease in the number of lesions in the aorta, the main artery carrying blood from the heart.
Using specific staining techniques on the aortas, the researchers were able to determine that the donor bone marrow cells "homed in" on areas where atherosclerotic lesions are most common, especially where smaller vessel branches take off from larger vessels. These areas tend to experience "turbulence" of blood.
When the researchers examined the vessels under a microscope, it appeared that the bone marrow cells not only migrated to where they were needed most, but that they differentiated into the proper cell types. Some turned into endothelial cells lining the arteries, while others turned into the smooth muscle cells beneath the endothelium that help strengthen the arteries.
To further prove that the donor bone marrow cells were responsible for rejuvenating arteries, the scientists measured in the endothelial cells the lengths of structures known as telomeres at the end of chromosomes. They found that the telomeres in the endothelial cells were longer in the treated mice than the untreated mice. Over time, telomeres are known to shorten as the organism ages.
The researchers also injected these atherosclerotic mice with donor cells from older mice as well as from younger, pre-atherosclerotic mice.
"We found that the bone marrow cells from the young mice had a nearly intact ability to prevent atherosclerosis, while the cells from the older mice did not," Goldschmidt explained. "This finding suggests that with aging, cells capable of preventing atherosclerosis that are normally present in the bone marrow became deficient in the older mice that had developed atherosclerosis."
Once the repair cells from the marrow become deficient, inflammation develops and leads to increase in inflammation markers (such as CRP). By providing competent bone marrow cells, the investigators were able to suppress the inflammation and its blood markers.
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