Modeling Hypertrophic Cardiomyopathy in a Dish

Posted on November 8th, 2018 by Dr. Francis Collins

Credit: Zhen Ma, University of California, Berkeley

Researchers have learned in recent years how to grow miniature human hearts in a dish. These “organoids” beat like the real thing and have allowed researchers to model many key aspects of how the heart works. What’s been really tough to model in a dish is how stresses on hearts that are genetically abnormal, such as in inherited familial cardiomyopathies, put people at greater risk for cardiac problems.

Enter the lab-grown human cardiac tissue pictured above. This healthy tissue comprised of the heart’s muscle cells, or cardiomyocytes (green, nuclei in red), was derived from induced pluripotent stem (iPS) cells. These cells are derived from adult skin or blood cells that are genetically reprogrammed to have the potential to develop into many different types of cells, including cardiomyocytes.

What’s different with this microtissue model is the cardiac tissue grows on and around a 3D scaffold (blue) made from synthetic fibers that mimic connective tissue collagen. The scaffold was built using laser-guided bioprinting technology. By precisely varying the thickness and stiffness of the individual fibers, the team mimics different degrees of stress that the heart may experience, for example, during exercise or in a person with high blood pressure.

This model is the work of a research team at the University of California, Berkeley, including Zhen Ma and Kevin Healy. They previously employed a similar process to produce developing human heart microchambers.

In the latest study, published in Nature Biomedical Engineering [1], the researchers went in a different direction. They explored how well-known genetic defects associated with the condition hypertrophic cardiomyopathy (HCM) affect the heart’s performance. In people with HCM, the walls of the heart’s ventricles thicken abnormally. The thickening limits the ability of the ventricles to fill properly, causing the heart’s electrical system to malfunction and putting people at greater risk of frequent dizzy spells, shortness of breath, chest pains, and even sudden death.

Healy and Ma’s team grew healthy and diseased cardiac tissues in their specially engineered dishes. The iPS cells used to grow the diseased tissues were gene-edited to carry a mutation leaving them deficient for a protein called cardiac myosin-binding protein C, or MYBPC3. A lack of this protein is associated with HCM.

To get a better idea of why, the team turned to its special microtissue model. The healthy heart tissue, when grown on the stiffer scaffold, adapted to the stronger contractions required to beat under the greater tension. That wasn’t the case for the diseased tissue that lacked MYBPC3. It generated less force, which became even more noticeable when the tissues were grown on thicker and stiffer scaffolds.

Previous studies suggested that MYBPC3 mutations cause malformations in fibers of the heart muscle. But this latest work indicates the mutations lead to mechanical problems in allowing the muscle fibers to contract, making the heart less efficient in pumping blood. It also shows that this disadvantage becomes even more pronounced when the heart is put under additional physical stress.

The researchers are now working with study co-author Bruce Conklin, Gladstone Institutes and University of California, San Francisco, to expand their research capabilities. They plan to produce a series of cardiac microtissues that carry genetic defects associated with various forms of cardiomyopathy.

They also plan to combine their new model with drug screening tools that will improve the heart’s pumping performance as part of the Tissue Chip for Drug Screening program. It’s a joint effort of NIH’s National Center for Advancing Translational Sciences, Food and Drug Administration (FDA), and the Defense Advanced Research Project Agency (DARPA). The hope is that these advances will point the way to new treatments for cardiomyopathies, which affect as many as 1 in 500 adults [2].

References:

[1] Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload . Ma Z, Huebsch N, Koo S, Mandegar MA, Siemons B, Boggess S, Conklin BR, Grigoropoulos CP, Healy KE. Nature Biomedical Engineering. September 10, 2018.

[2] Cardiomyopathy. Centers for Disease Control and Prevention, September 2, 2015.

Links:

Cardiomyopathy (National Heart, Lung, and Blood Institute/NIH)

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Stem Cell Information (NIH)

Healy Lab (University of California, Berkeley)

Ma Lab (Syracuse University, NY)

Conklin Lab (Gladstone Institutes and University of California, San Francisco)

NIH Support: National Heart, Lung, and Blood Institute; National Center for Advancing Translational Sciences