Summer 2015 - Research and Innovation

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Cardiac Stem Cell Research: Barth Syndrome

William Pu, MD

For cardiac researchers like William Pu, MD, advances in stem cell technology are ushering in a new era of possibility for treating heart disease.

Pu’s main focus is disease of the heart muscle. “Ideally, we would study heart muscle cells from human patients,” he says, “but there are significant obstacles.”

First, obtaining human heart muscle samples is not easy. “People are not lining up to donate heart cells,” Pu says. Second, once obtained, a sample is only viable for a few days because human heart muscle cells do not naturally divide.

Until recently, Pu and his colleagues relied largely on animal studies or studies of heart-specific proteins that are inserted into other kinds of human muscle cells. While both approaches have been useful, neither allows for studying how human diseases affect intact and functioning human heart muscle.

The rules of the game started to change in 2007.  That year, three research teams independently described how to take a human skin cell and reprogram it into a pluripotent stem cell that could be turned into any kind of cell and cultured indefinitely. Not only could researchers like Pu obtain heart muscle cells more easily and more frequently, but they were freed from the limitations of shelf life.

Pu jumped at the chance to apply this technology to his work on Barth syndrome, a mitochondrial disease that weakens the heart muscle.

After obtaining a skin sample from a patient with Barth syndrome, Pu was able to make stem cells from the patient’s skin cells, which he then turned into heart muscle cells. What was once skin became a beating heart muscle.

Next, Pu worked with Kevin Kit Parker’s bioengineering group at the Wyss Institute for Biologically Inspired Engineering to assemble the muscle cells on a tiny, flexible plastic film that instructs the cells to line up and form organized muscle fibers. When the cells are assembled into this “heart-on-a-chip” format, they are able to work together so their beating bends the plastic film. The amount of force the patient’s heart muscle generates can be measured by how much the sheet bends with each beat. Comparing a Barth syndrome patient’s sheet with one from a patient with a normally functioning heart further revealed that the Barth heart muscle cells were very weak compared to normal heart muscle cells. Thus, combining the stem cell and “heart-on-a-chip” technologies allowed Pu to model a patient’s disease in a culture dish.

Pu pushed onward to learn more about the disease process in Barth syndrome. “We have also studied the mechanisms of the disease,” he adds. “We’ve identified reactive oxygen species—toxic byproducts that sometimes build up in cells—as a causal factor for Barth Syndrome. By blocking reactive oxygen species with some drugs, we can turn the weak heart muscle into normally beating heart muscle.”

Pu’s team also showed in the chip model that replacing the mutant gene restores normal beating strength to Barth heart muscle tissue. This opened the door for experiments in gene therapy, and Pu says that initial work on mice with Barth syndrome has confirmed that gene therapy is very promising for this disease.

The field of translational stem cell research has certainly come a long way in a short amount of time.  Still, much remains in the realm of future possibility.  “Today we can take a patient’s cells, make stem cells, and correct a mutation,” says Pu. “But we cannot yet put these cells back into a patient’s heart to restore normal heart function.”

The possibility of creating a unique treatment for each patient based on his or her genetic makeup—a hallmark of the contemporary “precision medicine” movement—is also enticing, says Pu. However, he adds, “whether it could be used to actually personalize each patient’s treatment is something that still needs to be evaluated.”

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