Research team fixes broken hearts with stem cells

By Sherry Baker

A high school track star suddenly collapses during practice, his heartbeat inexplicably thrown into quivering, life-robbing chaos. How and why did his heart suddenly produce the electrical storm of deadly, irregular beats known as ventricular fibrillation, leading to sudden death?

This is the kind of mystery that could be unraveled in the Cellular Therapy Center at the VA Hospital. Emory researcher Samuel Dudley and colleagues Alice Huang and Mark Leimbach are working to unlock intracellular secrets of heart function.

Dudley’s team are the only scientists, as far as he knows, using gene targeting to manipulate stem cells from mice into perfect replicas of human cell mutations linked to arrhythmias. The result could be a new model for the study of cardiovascular disease—especially genetic disorders—and offers new hope for innovative treatments and potential cures.

Just the fact that heart cells are growing in the lab is remarkable. Cardiac electrophysiology researchers, who study and map the electrical landscape of the heart, have long been hampered by how quickly isolated heart cells die in a culture dish. But Dudley and his colleagues have developed techniques to overcome this problem.

“We don’t know exactly how this works yet and what all the triggers are, but if we can understand how heart cells develop, then we may be able to understand congenital heart defects,” said Dudley, assistant professor of medicine and physiology and chief of the VA’s cardiology division.

Dudley currently is studying Long QT syndrome and Brugada’s Syndrome (also known as idiopathic ventricular fibrillation), two potentially deadly autosomal dominant heart diseases.

“These diseases have been hard to study,” he said. “To do a clinical trial, you might have to find several families with this particular mutation and follow them for many years, waiting for a cardiac event. In the lab, we can see how heart cells with these mutations behave in the context of a normal action potential within three weeks.”

Although Long QT and Brugada’s syndromes are relatively rare diseases, Dudley said they may model more common acquired heart diseases. He and his team are studying the genetic manipulation of stem cells with an eye on additional future cardiac therapies, including growing replacement tissue for damaged hearts.

The researchers want to see if placing genetically altered cells in hearts can increase the strength of the organ and possibly repair the interior surface areas, or epithelium, of vessels injured by balloon angioplasty. Cell therapy also may prove useful in helping to prevent or alter restenosis, the reclogging of vessels after they’ve been opened by angioplasty.

Dudley feels stem-cell technology is even more promising than genetic therapy. “We can alter the genome of these cells before putting them into people—and we can do it in the culture dish, where we know exactly what we’ve done,” he said. “Unlike genetic therapies so far, this is a long-lasting change. We can even design cells sensitive to a certain medication so we can make sure the altered cells die on command if something goes wrong.”

Another advantage is the high likelihood that these cells, which do not express the immunologic markers associated with rejection, can be transplanted successfully from animals to humans. “The potential donor population is very great,” Dudley said.

In fact, Dudley questions whether stem-cell research might hold the key to why humans age—and how the process might be altered.

“In theory, aging is a stem cell function disorder,” he said. “It is becoming clear that the number of stem cells you have decreases by about 10 percent every decade of life. By the time you get to fairly old adulthood, you don’t have too many. So maybe the reason we all break down as we get older is that we don’t have enough stem cells floating around to fix us up again.

“There’s the possibility we could take stem cells out of your body, propagate them in the lab and expand them, then freeze them until you need them. I’m convinced that in the long term, this technology has an extremely high potential to alter not only cardiology therapies, but the basic landscape of medicine.”