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Embryonic cell-transplant therapies prevent heart arrhythmias in mice by restoring damaged heart tissue

One of the most dangerous and fatal consequences of heart attacks can be prevented with cell-transplant therapies, according to scientists at Cornell University, the University of Bonn and the University of Pittsburgh.

The discovery, published in the Dec. 5 issue of Nature, indicated that cell-transplant therapies have shown profound implications for restoring damaged heart tissue when living embryonic heart cells are transplanted into cardiac tissue of mice that had suffered heart attacks.

The paper's senior authors Michael Kotlikoff, the Austin O. Hooey Dean of Cornell's College of Veterinary Medicine, and Bernd Fleischmann at the University of Bonn, found that a protein called connexin43, expressed by the transplanted embryonic heart cells, improved electrical connections to other heart cells.

The researchers also proved that the improved connections helped activate the transplanted cells deep within the damaged section of the heart tissue, reversing the risk of developing ventricular arrhythmias after a heart attack, the number one cause of sudden death in the Western world.

"These results have important implications for therapy, although they must be verified in the context of naturally occurring heart damage. One can envision using a patient's own cells by deriving heart cells from stem cells to improve heart function and decrease arrhythmia risk," said Kotlikoff. "For the first time, we were able to see how cells used in therapy are working with other cells in a complex organ within a living animal, establishing the mechanism of the therapeutic effect."

In Kotlikoff's laboratory, the researchers determined that the transplanted embryonic cells were making electrical connections with normal heart cells. Using genetically modified heart cells that express a fluorescent sensor, they established that transplanted heart cells were activated during normal heart contractions.

While scientists recognize the untapped potential of using cell-based therapies to counter many debilitating diseases, they have not had tools to assess the function of the cells once transferred. Though cells from a human embryonic heart for transplantation could never be used, researchers at the University of Bonn engineered skeletal muscle to generate connexin43 and achieved the same restorative results as they did with the embryonic heart cells.

When Fleischmann and colleagues transplanted embryonic cardiac cells, the hearts' electrical stability and function returned to normal. Scientists have previously transplanted a variety of cell types into failing hearts with modest improvement of function, but transplanting skeletal muscle cells, however, made things worse and led to more arrhythmias.

Professor Guy Salama at the University of Pittsburgh School of Medicine was also able to map voltage signals across the surface of the hearts, establishing that the implanted cells improve conduction of electrical signals within the damaged heart tissue.

The study was funded by the National Institutes of Health, the Deutsche Forschungsgemeinschaft, the Federal Ministry of Education and Research, Germany, and the European Commission, Bonn Forschung.

by Krishna Ramanujan of the "Cornell Chronicle"