Published by
Stanford Medicine

Cardiovascular Medicine, Research, Stanford News, Stem Cells

Lab-made heart cells mimic common cardiac disease in Stanford study

Lab-made heart cells mimic common cardiac disease in Stanford study

Skin cells from a family with an inherited form of a common cardiac condition called dialated cardiomyopathy have been used to generate heart muscle cells in the Stanford laboratory of cardiologist Joseph Wu, MD, PhD. The cells, which are formed through a technique called induced pluripotency, mimic some features of the disease and serve as a canvas to test potential drug and gene therapy treatments for effectiveness and potential toxicity. The research, which was supported by the California Institute for Regenerative Medicine, is published today as the cover story in Science Translational Medicine. As described in our release:

The implications of such research are huge. According to Wu, one of the major reasons cardiac drugs are pulled from the market is unexpected cardiac toxicity — that is, they are damaging the very hearts they’re meant to help. Currently, such drugs are pre-screened for toxic effects on common laboratory cell lines derived from either hamster ovaries or human embryonic kidney cells. Even though these ovarian and kidney cells have been artificially induced to mimic the electrophysiology of human heart cells, they are still very different from the real thing. A reliable source of diseased and normal human heart cells on which to test the drugs’ effect prior to clinical use could improve drug screening, save billions of dollars and improve the lives of countless patients.

The family from which the researchers (including the study’s first author, postdoctoral scholar Ning Sun, MD, PhD) collected skin samples for study consists of three generations of affected individuals. The grandmother, two of three of her sons, and one of her grandsons all had the disease. The youngest, a 14-year-old boy, was so severely afflicted that he’s already had a heart transplant to alleviate his symptoms:

The researchers used iPS technology to convert skin cells from the affected and unaffected family members into stem cells, which they then coaxed to become heart muscle cells for further study. They then compared cells from unaffected family members with those who had the disease.

“We didn’t know exactly how the mutation carried in this family would impact the contractility of the cells,” said Sun. “Other studies had indicated that this mutation decreased calcium sensitivity in rodent cells, but we had no direct biochemical data on human cells. We were able to show that the force of contraction was lower in cells from patients with the mutation. We also saw that, as predicted in the rodent model, they were less responsive to calcium signaling.” (In a normal heart, rapid, periodic increases in calcium levels inside heart cells trigger each contraction.)

Wu and Sun also saw that the diseased cells exhibit structural differences and are more susceptible to mechanical stress than unaffected cells.

Dilated cardiomyopathy, in which the heart enlarges and loses its to contract effectively, is the leading cause of heart transplants in this country. Now the researchers would like to broaden their study:

“Next, we’d like to continue looking at cells from patients with other mutations associated with this disorder,” said Wu. “How do they behave in culture? Do they respond in the same way? What is the mechanism for their response? What changes if we selectively introduce different mutations into these cells? And how do we scale up drug screening using cardiac specific iPS cell lines?”

Previously: Setback for induced pluripotent stem cells, At new Stanford center, revealing dangerous secrets of the heart, iPS cells match embryonic stem cells in disease-modeling smackdown
Photo of iPS cells from human skin in the laboratory of UCLA’s Kathrin Plath, PhD, provided courtesy of the California Institute of Regenerative Medicine

Comment


Please read our comments policy before posting

Stanford Medicine Resources: