Stem-Cell Transplant Increases Oxygen In Damaged Heart (11/30/2007)

Scientists have determined that stem cells transplanted into a damaged heart can increase the presence of oxygen at the site of injury, suggesting that such transplants might someday be used as therapy after heart attacks and for other diseases characterized by a lack of oxygen.

A significant element of the finding was the method used to monitor oxygen. The results of the study mark the first noninvasive measurements of oxygen concentration in a beating heart after a stem-cell transplant through the use of electron paramagnetic resonance (EPR) imaging.

The EPR technology allowed researchers at The Ohio State University Medical Center to monitor oxygen concentration in the treated animal hearts for four weeks. During this time, oxygen levels in the treated area increased, scarring (myocardial infarction) was reduced and cardiac function improved.

The results were published in the October issue of the American Journal of Physiology - Heart and Circulatory Physiology.

"The key for any cell to survive is the presence of oxygen," noted Periannan Kuppusamy, director of the Center for Biomedical EPR Spectroscopy and Imaging at Ohio State and senior author of the study.

During a heart attack, when blood flow to the heart is blocked, the surrounding tissue rapidly loses oxygen and the heart muscle cells die.

Without treatment, the damaged muscle eventually weakens, leading to the development of congestive heart failure. Because cardiac cells are among the slowest in the body to replenish themselves, the transplantation of stem cells, which can turn into any cell, into the damaged heart tissue is an attractive therapy option.

An additional problem in attempting to reverse the weakening and degradation of the heart tissue using this technique is that the stem cells are transplanted into scarred tissue that receives little blood flow, meaning the tissue is low on the critical nutrients needed to allow cells to grow and divide. So far, research on stem-cell therapy in heart patients has yielded mixed results.

"Researchers are trying to find out why the transplanted cells are not surviving in some cases," said Kuppusamy, also an investigator in the Davis Heart and Lung Research Institute at Ohio State. "So we are asking, is the lack of oxygen in the damaged area responsible for the reduced survival of the stem cells? And how do you measure that in a deep organ like the heart?"

In the study, Kuppusamy and colleagues isolated skeletal myoblasts, the precursors to muscle cells, from mouse thighs. The researchers then induced a heart attack in other mice by blocking their left coronary arteries, which provide blood flow to the heart. Immediately after the simulated heart attack, they transplanted the stem cells into the damaged area of the heart.

In order to measure the oxygen content in the tissue after transplantation, the scientists labeled the stem cells with tiny probes that give off signals when exposed to oxygen. With EPR instrumentation that detects and measures those signals, the researchers monitored the oxygen level from the exact same location of each treated heart for four weeks. The oxygen measurements and cardiac function in hearts receiving a myoblast transplant were compared to both normal hearts and to hearts in which a heart attack was induced, but stem-cell therapy was not given.

They observed that transplantation of stem cells in the damaged region of the heart resulted in a significant increase in oxygen concentration (approximately 50 percent) when compared to the damaged region of untreated hearts, which were starved for oxygen. The stem cells also improved cardiac function, allowing the hearts to squeeze more blood with each beat. Finally, the stem cells promoted growth of new blood vessels in the damaged region of the heart, a promising sign that could lead to better blood flow, Kuppusamy said.

"We definitely use the promotion of blood vessel growth as a mark of the therapeutic nature of the cells," he said. "The 50 percent increase in oxygen concentration should be enough to let stem cells survive, but in humans, we may need even greater oxygen concentration to improve therapeutic outcome. We don't know yet."

Though questions remain about the long-term viability of transplanted stem cells, Kuppusamy said the ability to measure oxygen in the heart could eventually be extended beyond the lab.

"We know that to treat a heart attack, we need to increase oxygen concentration. But what is the best way to do that - medication, surgery, exercise? We can figure out the best therapy options by measuring oxygen during these activities," he said. Because the lack of oxygen is responsible for many disease processes, the oxygen measurement method holds promise for research in such diseases such as cancer, diabetes and peripheral vascular disease.

This research was supported by the National Institutes of Health. Other Ohio State researchers involved in the study were Mahmood Khan, Vijay Kumar Kutala, Deepti Vikram, Sheik Wisel, Simi Chacko, M. Lakshmi Kuppusamy, Iyyapu Mohan, Jay Zweier and Pawel Kwiatkowski.

Note: This story has been adapted from a news release issued by Ohio State University

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