The contribution of cellular mechanotransduction to cardiomyocyte form and function

Abstract

Myocardial development is regulated by an elegantly choreographed ensemble of signaling events mediated by a multitude of intermediates that take a variety of forms. Cellular differentiation and maturation are a subset of vertically integrated processes that extend over several spatial and temporal scales to create a well-defined collective of cells that are able to function cooperatively and reliably at the organ level. Early efforts to understand the molecular mechanisms of cardiomyocyte fate determination focused primarily on genetic and chemical mediators of this process. However, increasing evidence suggests that mechanical interactions between the extracellular matrix (ECM) and cell surface receptors as well as physical interactions between neighboring cells play important roles in regulating the signaling pathways controlling the developmental processes of the heart. Interdisciplinary efforts have made it apparent that the influence of the ECM on cellular behavior occurs through a multitude of physical mechanisms, such as ECM boundary conditions, elasticity, and the propagation of mechanical signals to intracellular compartments, such as the nucleus. In addition to experimental studies, a number of mathematical models have been developed that attempt to capture the interplay between cells and their local microenvironment and the influence these interactions have on cellular self-assembly and functional behavior. Nevertheless, many questions remain unanswered concerning the mechanism through which physical interactions between cardiomyocytes and their environment are translated into biochemical cellular responses and how these signaling modalities can be utilized in vitro to fabricate myocardial tissue constructs from stem cell-derived cardiomyocytes that more faithfully represent their in vivo counterpart. These studies represent a broad effort to characterize biological form as a conduit for information transfer that spans the nanometer length scale of proteins to the meter length scale of the patient and may yield new insights into the contribution of mechanotransduction into heart development and disease.

Fig. 1

Spatial scaling of the functional components of the heart The functional components of the myocardium demonstrate a hierarchical relationship that spans several orders of spatial magnitude, from the nanometer length scale of the proteins comprising actomyosin cross-bridges to the millimeter length sheets of laminar myocardial tissue that make up the muscular walls of the heart chambers. (adapted from Chien et al. 2008)

Fig. 2

Bi-directional signaling interfaces in the simplified myocardium a External mechanical cues are transmitted from the ECM to intracellular compartments via transmembrane integrin receptors that physically link it to the cytoskeleton. These mechanical signals elicit a number of biological responses ranging from ion channel activity to programmed cell death, and in turn these biological processes can feed information back to the extracellular space via the same mechanical pathway. b Transmembrane integrin receptors form a direct physical linkage between the ECM and the cytoskeleton through focal adhesions that provides a conduit for transmitting mechanical signals directly to intracellular compartments, such as the nucleus. c In addition to mechanotransduction through the integrin-ECM interface, cardiomyocytes also respond to mechanical signals from neighboring cells through intercellular junctions and direct transmembrane ligand-receptor interactions

Fig. 3

Comparison of myofibrillogenesis observed in primary and stem cell-derived cardiomyocytes in vitro with in silico simulations a NMVM on patterned FN at day 3 after seeding (i) square, (ii) circle; b Computational model of a (i) square and (ii) circular cell with myofibril mutual alignment turned on showing polarization in both cell shapes; c human iPS-derived cardiomyocytes on (i) patterned FN square, and (ii) isotropic FN; d Computational model of a (i) square and (ii) circular cell with myofibril mutual alignment turned off showing polarization only in the cell type with non-homogenous boundary conditions; (a, c) scale bar = 10μm; (b, d)color bar shows normalized traction stress (|T|) see Grosberg et al. (2011) for details on the model