Patients’ Skin Cells are Transformed into Heart Cells to Create a ‘Disease-In-A-Dish’
Researchers at the Johns Hopkins University School of Medicine and Sanford-Burnham Medical Research Institute in California have created a laboratory-grown cell model of an inherited heart condition known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The model was made by transforming skin cells from two patients with ARVD/C into heart cells using stem cell technology. The researchers were able, for the first time, to coax the cells to mature so that they would mimic the ARVD/C disease that strikes in adulthood.
An article describing the research, and its potential for facilitating the development of new treatments for the disease, is published online on January 27, 2013 by Nature.
"There is currently no treatment to prevent progression of ARVD/C, which is a rare inherited disorder that can cause sudden cardiac death, especially among young athletes. With this new model, we hope we are now on a path to developing better therapies for this life-threatening disease," says Daniel Judge, M.D., associate professor and medical director of the Center for Inherited Heart Diseases at the Johns Hopkins University School of Medicine and a study co-author.
Most people with ARVD/C don’t know they have it until they experience symptoms as young adults, including a heart rhythm abnormality, heart failure, or even sudden cardiac arrest due to arrhythmias caused by an enlarged and weakened right ventricle. Current treatments include medications, such as beta blockers, that are used to treat other heart conditions, as well as implantable cardiac defibrillators to shock the heart back into normal rhythm. Patients are told not to engage in rigorous, competitive athletic activities because the disease causes fatty scars in the heart that are exacerbated with exercise.
"It’s tough to demonstrate that a disease-in-a-dish model is clinically relevant for an adult-onset disease. But we made a key finding here - we can recapitulate the defects in this disease only when we induce adult-like metabolism. This is an important breakthrough considering that ARVD/C symptoms usually don't arise until young adulthood. Yet the stem cells we’re working with are embryonic in nature," says Huei-Sheng Vincent Chen, M.D., Ph.D., associate professor at Sanford-Burnham and senior author of the study.
To recreate ARVD/C heart cells in the lab, the research team first obtained skin samples from ARVD/C patients at Johns Hopkins, which is home to one of the largest ARVD/C patient registries in the world. They added genetic materials to the adult skin cells to dial back the developmental clock, producing embryonic-like induced pluripotent stem cells (iPSCs), which are capable of developing into any type of cells. The researchers then coaxed the iPSCs into producing an unlimited supply of patient-specific heart muscle cells. These heart cells were largely embryonic in nature, but carried the original patient’s genetic mutations.
For nearly a year, no matter what they tried, the team couldn’t get their ARVD/C heart muscle cells to show any signs of the disease. Without those signs, these young muscle cells were of no value for studying the disease or testing new therapeutic drugs.
With further study, however, the team discovered that the type of energy used by the cells was the key to inducing signs of ARVD/C, an adult disease, in their embryonic-like cells. Human fetal heart muscle cells use glucose (sugar) as their primary source of energy. In contrast, adult heart muscle cells prefer using fat for energy production. So Chen’s team applied several chemical cocktails to trigger this shift to adult metabolism in their model and found that metabolic malfunction is at the core of ARVD/C disease.
Chen’s team eventually tracked down the final piece of the puzzle to make patient-specific heart muscle cells behave like sick ARVD/C heart cells: the abnormal overactivation of a protein called PPAR , a critical element in the body’s regulation of fatty acids and glucose metabolism. With the newly established model, they not only replicated ARVD/C diseased cells in a dish, but also were able to test new potential drug targets for treating the disease.
"This unique model of ARVD/C not only helped us better understand how the disease develops, we used it to block two pathways in the development of the diseased cells, preventing the progression of the disease. Now, we can explore using these pathways to create effective treatments for ARVD/C," says Judge.
The research was funded by the California Institute of Regenerative Medicine (grants RS1-00171-1, RB2-01512, and RB4-06276) and the U.S. National Institutes of Health (National Heart, Lung, and Blood Institute grant RO1HL105194).