The research team, led by Donald Orlic, Ph.D., a staff scientist in the genetics and molecular biology branch of the Division of Intramural Research at the National Human Genome Research Institute (NHGRI), and Piero Anversa, M.D., professor of medicine and director of the Cardiovascular Research Institute at New York Medical College, reported their results in the April 4, 2001, issue of Nature.
"This study offers hope that we might one day be able to actually reverse the damage caused by a heart attack," says NHGRI Director Francis S. Collins, M.D., Ph.D. "The apparent ability of stem cells in the bone marrow of adult animals to rebuild the heart reveals nature's remarkably flexible response to disease."
"Our results indicate the great potential of adult stem cells to differentiate into other cell types and repair a damaged organ, a property commonly attributed to embryonic stem cells," Anversa says. "This may allow us to utilize a patient's own stem cells as a new therapeutic option."
Typically, stem cells can be found in various tissues, such as muscle and skin, where they continuously replenish lost cells. Bone marrow stem cells usually produce blood elements, such as red and white blood cells. A growing body of research, however, suggests that stem cells - both embryonic and adult - retain the ability to differentiate into a wider array of body tissues that may be used as a cellular therapy to treat disease.
Heart attacks provide an important target for this treatment because they are a leading cause of death. About 1.1 million Americans will suffer a heart attack this year; some 450,000 will die. A heart attack occurs when the coronary arteries that carry blood to the heart muscles become blocked. The interruption in the blood supply suffocates the heart muscle cells below the blockage, substantially reducing the heart's ability to pump blood. Typically, if more than 40 percent of the left ventricle (the main pumping chamber of the heart) is damaged, the patient ultimately dies.
In their search for a way to reverse the damage, the team began by isolating bone marrow stem cells from male mice. The isolated stem cells carried a newly inserted gene that produces green fluorescent protein, a marker that enabled the researchers to identify the transplanted cells. In addition, the researchers decided to transplant stem cells from male mice into female hearts so they could show definitively that any new heart muscle had come from donor cells.
The researchers then gave the female mice a heart attack by tying a suture around a coronary artery commonly blocked in human disease. A short time later, they injected the labeled stem cells into the heart muscle next to the damaged tissue. Remarkably, over the next seven to 11 days, the stem cells began to multiply and transform themselves into heart muscle cells and migrated into the damaged area. After an average of nine days, the newly formed heart muscle cells occupied 68 percent of the damaged portion of the heart. In addition, the stem cells also began producing smooth muscle cells and endothelial cells that organized themselves into new blood vessels.
"Initially, I thought if there was a little regeneration, some heart muscle cells forming, then that would be considered successful," NHGRI's Orlic says. "Instead, our expectations were far exceeded in terms of seeing not just heart muscle cells, but blood vessels and functional measurements showing that the repair actually improved cardiac output. It was a wonderful surprise and went far beyond our expectations."
Still, the treatment only worked in 12 of 30 mice, about 40 percent. That may be due to the difficulty of injecting the stem cells into a heart that beats on the average of 600 times per minute. New research is already underway to resolve these questions.
New York Medical College's Anversa predicts that if follow-up studies go well, clinical trials in human patients could begin in three years. "The restoration in the heart's ability to pump blood could well be clinically significant," he says.
In addition to Orlic and Anversa, co-authors of the study include: Stacie M. Anderson and David M. Bodine of NHGRI; Jan Kajstura, Stefano Chimenti, Igor Jakoniuk, Baosheng Li, Bernardo Nadal-Ginard, Annarosa Leri of New York Medical College and James Pickel and Ronald McKay of the National Institute of Neurological Disorders and Stroke, NIH.
In addition to the support from the NHGRI, this work was also funded by grants from the National Heart, Lung and Blood Institute and the National Institute on Aging.
For additional information, including a graphic showing the procedure and high-resolution images of the regenerating cells, go to http://www.nhgri.nih.gov/NEWS/news.html.