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Mechanosensitivity and compositional dynamics of cell-matrix adhesions.

ABSTRACT: Cells perceive information about the biochemical and biophysical properties of their tissue microenvironment through integrin-mediated cell-matrix adhesions, which connect the cytoskeleton with the extracellular matrix and thereby allow cohesion and long-range mechanical connections within tissues. The formation of cell-matrix adhesions and integrin signalling involves the dynamic recruitment and assembly of an inventory of proteins, collectively termed the 'adhesome', at the adhesive site. The recruitment of some adhesome proteins, most notably the Lin11-, Isl1- and Mec3-domain-containing proteins, depends on mechanical tension generated by myosin II-mediated contractile forces exerted on cell-matrix adhesions. When exposed to force, mechanosensitive adhesome proteins can change their conformation or expose cryptic-binding sites leading to the recruitment of proteins, rearrangement of the cytoskeleton, reinforcement of the adhesive site and signal transduction. Biophysical methods and proteomics revealed force ranges within the adhesome and cytoskeleton, and also force-dependent changes in adhesome composition. In this review, we provide an overview of the compositional dynamics of cell-matrix adhesions, discuss the most prevalent functional domains in adhesome proteins and review literature and concepts about mechanosensing mechanisms that operate at the adhesion site.

SUBMITTER: Schiller HB

PROVIDER: S-EPMC3674437 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Project description:Adhesion between cardiac myocytes is essential for the heart to function as an electromechanical syncytium. Although cell-matrix and cell-cell adhesions reorganize during development and disease, the hierarchical cooperation between these subcellular structures is poorly understood. We reasoned that, during cardiac development, focal adhesions mechanically stabilize cells and tissues during myofibrillogenesis and intercalated disc assembly. As the intercalated disc matures, we postulated that focal adhesions disassemble as systolic stresses are transmitted intercellularly. Finally, we hypothesized that pathological remodeling of cardiac microenvironments induces excessive mechanical loading of intercalated discs, leading to assembly of stabilizing focal adhesions adjacent to the junction. To test our model, we engineered ?tissues composed of two ventricular myocytes on deformable substrates of tunable elasticity to measure the dynamic organization and functional remodeling of myofibrils, focal adhesions, and intercalated discs as cooperative ensembles. Maturing ?tissues increased systolic force while simultaneously developing into an electromechanical syncytium by disassembling focal adhesions at the cell-cell interface and forming mature intercalated discs that transmitted the systolic load. We found that engineering the microenvironment to mimic fibrosis resulted in focal adhesion formation adjacent to the cell-cell interface, suggesting that the intercalated disc required mechanical reinforcement. In these pathological microenvironments, ?tissues exhibited further evidence of maladaptive remodeling, including lower work efficiency, longer contraction cycle duration, and weakened relationships between cytoskeletal organization and force generation. These results suggest that the cooperative balance between cell-matrix and cell-cell adhesions in the heart is guided by an architectural and functional hierarchy established during development and disrupted during disease.

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Mechanosensitivity and compositional dynamics of cell-matrix adhesions.

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