New evidence suggests that a promising investigational treatment for patients with damaged hearts -- using adult stem cells to regenerate heart tissue -- may not work as planned. In the December 2004 issue of the Journal of Clinical Investigation, researchers from the University of Chicago show that although stem cells derived from bone marrow can find their way to areas of damaged heart muscle, infiltrate into these regions and proliferate, they do not mature into new cardiac muscle cells.
A series of previous studies suggested that stem cells from bone marrow could be induced to become cardiac muscle, replacing damaged tissue and potentially restoring heart function. This series of more-rigorous experiments, however, found that the transplanted cells are unable to take the crucial final steps. They do not produce a muscle protein called sarcoglycan, which is necessary for normal heart and skeletal muscle function.
The failure of these cells to express this protein "severely limits their utility for cardiac and skeletal muscle regeneration," the authors note.
"This was a complete surprise, and a considerable disappointment," said study director Elizabeth McNally, M.D., Ph.D., associate professor of medicine at the University of Chicago. "We set out to confirm, using more stringent criteria, the very appealing strategy of using stem cells from bone marrow to regenerate cardiac muscle, but we found that they never become normal, mature muscle cells."
The researchers used bone marrow side population cells (BM-SP), a sub-set of the stem cells found in marrow. Earlier studies demonstrated that these cells could home in on areas of damaged muscle and suggested that they matured into working skeletal or cardiac muscle cells. Clinical trials of this approach are already underway in patients who have had a heart attack and initial results have been "promising."
Despite high hopes for such cellular self-renewal, however, many researchers remained skeptical about the capacity of adult stem cells, even BM-SP cells, to complete the transition. McNally, a cardiologist who studies the genetics of muscle disease, realized that mice in her lab that lack a receptor called g-sarcoglycan, normally found on the surface of muscle cells, provided the perfect test of this approach.
Mice born without a functioning g-sarcoglycan gene have multiple tiny heart attacks that produce "microinfarcts," small regions of degeneration. So McNally and colleagues collected BM-SP cells from normal male mice and injected them into female mice that lacked sarcoglycan.
By tracing the male Y chromosomes -- found only in the donated BM-SP cells -- they discovered that the injected cells located the areas of muscle damage and insinuated themselves, sometimes as separate cells and sometimes by fusing with muscle cells.
In neither case, though, did they produce sarcoglycan, a reliable marker of mature muscle cells. When the researchers repeated the experiment with whole bone marrow, rather than isolated BM-SP cells, they got identical results.
They were slightly more successful with skeletal muscle. After examining 10,000 muscle fibers from each of 14 mice they found two myofibers that contained sarcoglycan.
These results are difficult to reconcile with the promising responses seen in mice and humans treated with adult stem cells.
"It's clear that the transplanted cells aren't growing, as we once hoped, into heart cells," McNally said, "but they may stimulate the growth of new blood vessels into the damaged regions or they may secrete growth factors that promote recovery."
If we can figure out what is actually going on in these patients and understand the mechanism, she added, we might be able to design a more effective approach.
The next step may be to find more flexible sources of injectable cells. Although readily available, BM-SP cells appear to have limited potential. Several researchers are trying to isolate a putative cardiac stem cell, which could mature into functional heart muscle. Embryonic stem cells also are an option.
"The whole idea of regenerative cellular medicine is very attractive," said McNally. "Many of the diseases that most concern us involve degeneration of the heart or the brain. The notion of replacing those cells has a lot of appeal. But it does not look like stem cells from bone marrow are going to make that realistic for patients with heart failure any time soon."
The Muscular Dystrophy Association, the National Institutes of Health, the American Heart Association and the Burroughs Welcome Fund supported this study. Authors include Karen Lapidos, Yiyin Chen, Judy Earley, Ahike Heydemann and Jill Huber of the University of Chicago and Marcia Chien and Averil Ma of the University of California at San Francisco.
Copyright © 2004 University of Chicago Hospitals.
Lapidos KA, Chen YE, Earley JU, Heydemann A, Huber JM, Chien M, Ma A, McNally EM.
Transplanted hematopoietic stem cells demonstrate impaired sarcoglycan expression after engraftment into cardiac and skeletal muscle.
J Clin Invest. 2004 Dec;114(11):1577-85.
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