In Vitro Methods to Model Cardiac Mechanobiology in Health and Disease

In vitro cardiac modeling has taken great strides in the past decade. While most cell and engineered tissue models have focused on cell and tissue contractile function as readouts, mechanobiological cues from the cell environment that affect this function, such as matrix stiffness or organization, are less well explored. In this study, we review two-dimensional (2D) and three-dimensional (3D) models of cardiac function that allow for systematic manipulation or precise control of mechanobiological cues under simulated (patho)physiological conditions while acquiring multiple readouts of cell and tissue function. We summarize the cell types used in these models and highlight the importance of linking 2D and 3D models to address the multiscale organization and mechanical behavior. Finally, we provide directions on how to advance in vitro modeling for cardiac mechanobiology using next generation hydrogels that mimic mechanical and structural environmental features at different length scales and diseased cell types, along with the development of new tissue fabrication and readout techniques. Impact statement Understanding the impact of mechanobiology in cardiac (patho)physiology is essential for developing effective tissue regeneration and drug discovery strategies and requires detailed cause-effect studies. The development of three-dimensional in vitro models allows for such studies with high experimental control, while integrating knowledge from complementary cell culture models and in vivo studies for this purpose. Complemented by the use of human-induced pluripotent stem cells, with or without predisposed genetic diseases, these in vitro models will offer promising outlooks to delineate the impact of mechanobiological cues on human cardiac (patho)physiology in a dish.