Effects of maturation factors on the mechanics and electrophysiology of 3D engineered cardiac microtissues*

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) represent a potentially unlimited source of cells that can be used for cardiac regeneration and cardiac disease modeling. However, hiPSC-CMs as currently used remain fundamentally immature. We have developed three-dimensional (3D) engineered cardiac microtissues (CMTs) grown on magnetically actuated microfabricated tissue gauges, which enable assessment of the physical and electrophysiological characteristics of the hiPSC-CMs through measurements of their force generation and mechanical response to electrical and chemical perturbations. Using combinations of defined chemical factors including triiodothyronine hormone, we have demonstrated structural maturation of hiPSC-CMs in CMTs, including improved alignment and well-defined sarcomeres more similar to adult CMs than untreated cells. The treated CMTs show enhanced static and dynamic force generation, and increased spontaneous contraction frequency. Measurements of conduction velocity via voltage-sensitive optical mapping show that the CMTs are well coupled electrically. These 3D hiPSC-CMTs can serve as a platform for exploration of the physical manifestations of genetically based cardiac diseases.