Patients’ own skin cells are transformed into heart cells to create “disease in a dish”

By Heather Buschman, Ph.D.
January 27, 2013
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Most patients with an inherited heart condition known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) don’t know they have a problem until they’re in their early 20s. The lack of symptoms at younger ages makes it very difficult for researchers to study how ARVD/C evolves or to develop treatments.

A new stem cell-based technology created by 2012 Nobel Prize winner Shinya Yamanaka, M.D., Ph.D., helps solve this problem. With this technology, researchers can generate heart muscle cells from a patient’s own skin cells. However, these newly made heart cells are mostly immature. That raises questions about whether or not they can be used to mimic a disease that occurs in adulthood.

In a paper published January 27 in Nature, researchers unveil the first maturation-based “disease in a dish” model for ARVD/C. The model was created using Yamanaka’s technology and a new method to mimic maturity by making the cells’ metabolism more like that in adult hearts. For that reason, this model is likely more relevant to human ARVD/C than other models and therefore better suited for studying the disease and testing new treatments.

“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,” said Huei-Sheng Vincent Chen, M.D., Ph.D., associate professor at Sanford-Burnham and senior author of the study.

Huei-Sheng Vincent Chen

To establish this model, Chen teamed up with expert ARVD/C cardiologists Daniel Judge, M.D., Joseph Marine, M.D., and Hugh Calkins, M.D., at Johns Hopkins University. Johns Hopkins is home to one of the largest ARVD/C patient registries in the world.

“There is currently no treatment to prevent progression of ARVD/C, a rare disorder that preferentially affects athletes. With this new model, we hope we are now on a path to develop better therapies for this life-threatening disease,” said Judge, associate professor and medical director of the Center for Inherited Heart Disease at the Johns Hopkins University School of Medicine.

Disease in a dish

To recreate a person’s own unique ARVD/C in the lab, the team first obtained skin samples from ARVD/C patients with certain mutations believed to be involved in the disease. Next they performed Yamanaka’s technique: adding a few molecules that dial back the developmental clock on these adult skin cells, producing embryonic-like induced pluripotent stem cells (iPSCs). 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 along the original patient’s genetic mutations.

However, 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 actual signs of adult-onset ARVD/C, these young, patient-specific heart muscle cells were no use for studying the disease or testing new therapeutic drugs.

Speeding up time

Eventually, the team experienced the big “aha!” moment they’d been looking for. They discovered that metabolic maturity is 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 cocktails to trigger this shift to adult metabolism in their model.

After more trial and error, they discovered that metabolic malfunction is at the core of ARVD/C disease. Moreover, Chen’s team tracked down the final piece of puzzle to make patient-specific heart muscle cells behave like sick ARVD/C hearts: the abnormal over-activation of a protein called PPARg. Scientists previously attributed ARVD/C to a problem in weakened connections between heart muscle cells, which occur only in half of the ARVD/C patients. With the newly established model, they not only replicated this adult-onset disease in a dish, but also presented new potential drug targets for treating ARVD/C.

What’s next?

Chen’s team was recently awarded a new grant from the California Institute for Regenerative Medicine to create additional iPSC-based ARVD/C models. With more ARVD/C models, they will determine whether or not all (or at least most) patients develop the disease via the same metabolic defects discovered in this current study.

Together with the Johns Hopkins team, Chen also hopes to conduct preclinical studies to find a new therapy for this deadly heart condition.

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This 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).

Original paper:

Kim, C., Wong, J., Wen, J., Wang, S., Wang, C., Spiering, S., Kan, N., Forcales, S., Puri, P., Leone, T., Marine, J., Calkins, H., Kelly, D., Judge, D., & Chen, H. (2013). Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs Nature DOI: 10.1038/nature11799

Media contacts:

Heather Buschman, Ph.D.
Sanford-Burnham Medical Research Institute
hbuschman@sanfordburnham.org

(858) 795-5343

Shawna Williams
Johns Hopkins University
shawna@jhmi.edu

(410) 955-8236

ResearchBlogging.org

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About Author

Heather Buschman, Ph.D.

Heather was an SBP Communications staff member.

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7 Comments

  1. Lynn Stoppelman on

    In 1994 my ARVD website first started reaching out to families and patients who had no network and sparse information about this life-threatening disease. It has taken almost twenty years, but with this breakthrough via stem cell research it appears that collaborative scientists are close to disrupting this fierce disease. Truly a sign of hope, thank you!

    • My husband, who is a 54 year old male, has ARVD and now doctors suspect one of our three sons may have it due to his recent CT scan. Our son is a healthy 16 year old male who enjoys outdoor sports especially football. My husband is currently treated with the wonderful doctors at Mayo Clinic and we so appreciate them, however we are wondering if earlier diagnosis and radical treatment is available and where? Thank you.!!

      • Patrick Bartosch on

        Hello!

        Thank you for your comment and I’m very sorry to hear your husband has ARVD and, potentially, one of your sons. We at Sanford-Burnham do basic medical research, which means we’re looking into the molecular causes of disease. We mostly do not work with patients and we usually don’t do clinical trials. I recommend you speak with your doctor and/or cardiologist about this. He or she may know what treatments and trials are available. You may also want to check out clinicaltrials.gov.

  2. Pingback: EMAILS & NEWSLETTERS FORUM | NHLBI in the News � February 8, 2013

  3. Ce sont avec des chercheurs de cette trempe q’un jour la maladie si cruelle reculera , je pense en particulier à nombre de nos jeunes fauchés dans leur élan vital, j’émets le voeux que cela soit réalisable sur le terrain le plus rapidement possible, nous gens de peu , nous nous épuisons à aider au mieux les rescapés et les familles concernés par de tels drames , merci à NHLBI de véhiculer ce genre de bonnes nouvelles , nous en redemandons!!….. Bravo et chapeau bas aux chercheurs!.

    • Heather Buschman, Ph.D. on

      Thank you for the lovely comment, Pichon!

      Here is the English version, via Google Translate:
      It is with researchers of this caliber are Features day so cruel disease recede, I think in particular of our young people broke their élan vital, I express the wish that it be feasible on the ground as quickly as possible, us little people, we exhaust ourselves to better assist survivors and families affected by such tragedies, thank you to NHLBI to convey this kind of good news, we redemandons! ….. Congratulations and hats off to research!.

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