Micromechanobiology: Focusing on the Cardiac Cell–Substrate Interface

Abstract

Engineered, in vitro cardiac cell and tissue systems provide test beds for the study of cardiac development, cellular disease processes, and drug responses in a dish. Much effort has focused on improving the structure and function of engineered cardiomyocytes and heart tissues. However, these parameters depend critically on signaling through the cellular microenvironment in terms of ligand composition, matrix stiffness, and substrate mechanical properties—that is, matrix micromechanobiology. To facilitate improvements to in vitro microenvironment design, we review how cardiomyocytes and their microenvironment change during development and disease in terms of integrin expression and extracellular matrix (ECM) composition. We also discuss strategies used to bind proteins to common mechanobiology platforms and describe important differences in binding strength to the substrate. Finally, we review example biomaterial approaches designed to support and probe cell–ECM interactions of cardiomyocytes in vitro, as well as open questions and challenges.

3D Microwell Platforms for Control of Single Cell 3D Geometry and Intracellular Organization

“…34,47,48 For instance, cytoskeletal proteins can interact with integrins through intermediate proteins, altering intracellular structure. 10 In addition, signaling molecules can be sequestered in adhesion complexes, affecting gene expression. Future work is needed to fully characterize whether ligand type and density are differentially sensed in 3D vs. 2D configurations.…”

3D Microwell Platforms for Control of Single Cell 3D Geometry and Intracellular Organization

“…34,47,48 For instance, cytoskeletal proteins can interact with integrins through intermediate proteins, altering intracellular structure. 10 In addition, signaling molecules can be sequestered in adhesion complexes, affecting gene expression. Future work is needed to fully characterize whether ligand type and density are differentially sensed in 3D vs. 2D…”

The harder the climb the better the view: The impact of substrate stiffness on cardiomyocyte fate

“…In the rat myocardium, both collagen I and III expression rises throughout the fetal, neonatal, and adult stages [10]. Collagen I expression can dramatically change during aging or injured myocardium [11]. Interestingly, collagen IV is the only collagen secreted by cardiomyocytes and is mainly collected in the basal membrane in association with laminin and fibronectin [12,13].…”

“…Adding further complexity, the extracellular and intracellular components undergo spatial and temporal changes during cardiac development. Throughout the lifespan from embryonic to adult stage [44], the architecture and the composition of cECM undergo continuous cellmediated turnover, ensuring the dynamic remodelling of the cECM niche [5,11,14,45]. It is well known that cardiac fibroblasts are the main source of depositing proteins within the cECM to form a network around cells that reinforces cardiac architecture.…”