Stressing heart cells to study disease

Engineered tissues that mimic the human heart are used to study this organ and its diseases. When immature cardiac cells are aligned in a 3D structure resembling the heart, they behave more like in vivo heart muscle than those cultured in 2D.

To investigate why this occurs, Simmons et al. examined how mechanical tension generated across 3D tissues formed by aligned heart muscle cells influences their electrical conduction. They found that sodium channels and gap junctions, two key players in electrical conduction, are turned on in cells under tension, allowing cells to adapt by changing their action potential.

“Mechanical tension can be leveraged to make cardiomyocytes derived from induced pluripotent stem cells more electrically mature. This can be leveraged for disease modeling,” said author Nathaniel Huebsch.

Arrhythmogenic cardiomyopathy is a genetically inherited disease associated with mutations in cell-cell junctions that causes young athletes to develop deadly arrhythmias. It is challenging to model this disease with induced pluripotent stem cells because stem cell-derived heart muscle is typically immature, causing even healthy cells to show features of this disease, including poor conduction and sodium channel dysfunction.

The authors used mechanical tension to trigger the characteristics of arrhythmogenic cardiomyopathy in stem cell-derived heart muscle. They found cells with cell-cell junction mutations adapted to increased tension through action potential changes primarily by altering calcium rather than sodium ion influx.

“This may be part of why mutations in cell-cell junctions make patients prone to develop arrhythmogenic heart disease,” Huebsch said.

Next, the authors want to understand the mechanisms through which tension regulates ion channel function. They also plan to study potential therapies for arrhythmogenic heart diseases like arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy.

Source: “Engineered tissue geometry and Plakophilin-2 regulate electrophysiology of human iPSC-derived cardiomyocytes,” by Daniel W. Simmons, Ganesh Malayath, David R. Schuftan, Jingxuan Guo, Kasoorelope Oguntuyo, Ghiska Ramahdita, Yuwen Sun, Samuel D. Jordan, Mary K. Munsell, Brennan Kandalaft, Missy Pear, Stacey L. Rentschler, and Nathaniel Huebsch, APL Bioengineering (2024). The article can be accessed at https://doi.org/10.1063/5.0160677 .