Self-Organization of Muscle Cell Structure and Function

Abstract

The organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomere to the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain the muscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized that boundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directed sarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytes organizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyte shape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: the interaction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundling of nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractile cytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated by extracellular boundary conditions, is required to polarize the contractile cytoskeleton.

Cyclic strain induces dual-mode endothelial-mesenchymal transformation of the cardiac valve

“…We quantified the actin alignment ( Fig. S2A) with an analysis technique adapted from crystallography (29) to quantify the probability that actin fibers would be coaligned, termed the orientational order parameter (OOP) (30). The actin OOP was significantly greater in anisotropic engineered endothelium stretched 10% parallel to the longitudinal direction versus the actin OOP in the other conditions (Fig.…”

“…Actin OOP, nuclear eccentricity, and cell aspect ratio were based on computational analyses of immunostained images (30,58). The OOP was developed for the study of organization of liquid crystals (29) and adapted for biological applications (59), and was computed from the pixel-based orientation vectors of the actin images.…”

Mathematical modelling of active contraction in isolated cardiomyocytes

“…In fact diseased myocardium is usually studied throughout interaction between cells and stiff substrates, analysing the increase in force generation, remodelling and adhesion. Extracellular space conditions have been further hypothesized to potentiate the organization of cytoskeletal scaffolds and the contractile response as well (Grosberg et al, 2011). Moreover, focal adhesions have been recently proposed to mechanically stabilize myocyte form and functions (McCain et al, 2012) by analysing stiff micro-environment effects on the intrinsic myocyte loading.…”

“…The leading ideas consider muscular organization as the product of a full functional adaptation of the cell spanning from the sarcomere to the muscle bundle (Sheehy et al, 2012). Through such an approach boundary constraints in the extracellular space have been recognized to potentiate the organization of cytoskeletal scaffolds for sarcomerogenesis, generating a positive feedback loop which polarizes the contractile cytoskeleton towards the functional organization of the tissue (Grosberg et al, 2011). Moreover, cell-cell and cell-matrix adhesions have been suggested to cooperate for the cardiac function as an electromechanical syncytium (McCain et al, 2012).…”

“…These processes play a key role in the overall cardiac function, and therefore understanding of these mechanisms can be of utmost importance and interest for the study of many physiological and pathological heart conditions (Hatano et al, 2011;Bers, 2002). Several systemic effects of cardiac mechano-electric interactions can be studied by regarding elastic properties of isolated cardiac myocytes (Iribe et al, 2009;Grosberg et al, 2011;McCain et al, 2012;Sheehy et al, 2012). Experimental evidences (Deshpande et al, 2006) highlight that the largest forces recorded are often present at locations where no visible stress fibres exist.…”