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  • Review Article
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Balancing forces: architectural control of mechanotransduction

Key Points

  • Cells have complex machinery capable of sensing and responding to mechanical cues from their microenvironment through a process termed mechanotransduction. These cues are typically sensed through force-induced conformational or organizational changes to molecules or structures such as ion channels, cadherin complexes, G protein-coupled receptors, Tyr kinase receptors and integrins, which, upon activation, ultimately trigger downstream signalling pathways that modify cell fate.

  • The interwoven mechanical interactions between neighbouring cells and between cells and their extracellular matrix, as well as through adhesion and filament networks, determine local forces and sites of mechanotransduction. Cumulatively, these nanoscale-level to tissue-level interactions define a cell's mechanical context and provide a high level of control over cellular mechanotransduction and resulting cell behaviour.

  • Mechanical cues have an integral role in directing development, as cell shape and motility are essential for many of the fundamental processes that are involved in embryogenesis. A crucial structural component that directs the mechanical phenotype of tissues during development is the extracellular matrix: its physical state and rigidity direct developmental processes such as cell sorting, differentiation and compartmentalization.

  • Mechanotransduction occurs on a relatively fast timescale, on the order of microseconds to minutes. By contrast, many pathological states, such as cardiovascular disease and cancer, derive from sustained perturbations to mechanotransduction over longer periods of time, lasting months or even years. The extracellular matrix, by virtue of its ability to be dynamically remodelled, is a prime candidate for maintaining these perturbations.

  • The extracellular matrix is a highly stable system that can be equated to a type of memory-storage device that can be 'read' or 'written-to' by cells. In this analogy, information is written to the extracellular matrix by crosslinking enzymes, including lysyl oxidase, and matrix metalloproteinases. Corruption of information through unregulated modifications to the extracellular matrix can be misread by cells, leading to tumour growth, inflammation and metastasis.

Abstract

All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

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Figure 1: The mechanical network.
Figure 2: Spatio-mechanical regulation of signalling pathways.
Figure 3: The extracellular matrix and tensional homeostasis in development.
Figure 4: Sustaining mechanotransduction.
Figure 5: Tensional homeostasis in tumour progression.

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Acknowledgements

We apologize to all colleagues whose work cannot be cited owing to space limitations. This work was supported by the Breast Cancer Research Program of the US Department of Defense Era of Hope grant W81XWH-05-1-0330, US National Cancer Institute (NCI) grants U54CA143836-01, and US National Institutes of Health (NIH) NCI R01 CA138818-01A1 (to V.M.W.), as well as NIH NCI Breast Spore P50CA58207, which provided support for C.C.D.

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Glossary

Kartagener's syndrome

A developmental disorder in which a disruption to mechanotransduction signalling by cilia-driven fluid flow results in the mirror-image reversal of internal organs.

Hutchinson–Gilford progeria syndrome

A disorder that is characterized by the rapid and dramatic appearance of ageing. The disease results from a genetic condition in which an abnormal version of the lamin A protein is produced, resulting in a highly unstable nuclear envelope. This is hypothesized to result in a disruption to mechanotransduction in vascular cells, contributing to arteriosclerosis, the leading cause of death for patients with this disease.

Mechanotransduction

The process through which cells sense and respond to their mechanical environment, such as the extracellular matrix, adjacent cells or external stresses. During mechanotransduction, mechanical signals are sensed and activate intracellular biochemical signalling pathways.

Actomyosin

Actin is one of the principal components of the cytoskeleton and forms a network of filaments with a class of molecular motors called myosins. The actomyosin network is best known for its role in contractility and force generation.

Interstitial flow

Present in all living systems, this type of fluid flow produces small currents through tissues and the extracellular matrix and is driven by dynamic stress.

Transcellular

Whereas 'paracellular' delineates processes occurring between cells, transcellular describes processes occurring through cells. One example is in transcellular transport, where molecules are moved through an epithelial cell layer.

Epithelial–mesenchymal transitions

Instances of a developmental programme that is hypothesized to be activated in metastasis and proliferation. This transition is characterized by an enhanced migratory capacity, loss of cell adhesion, the downregulation of E-cadherin, and a malignant phenotype.

Stomodeal primordium

In Drosophila melanogaster, the stomodeal primordium separates the anterior midgut from the middle germ layer, the mesoderm.

Gastrulation

A developmental change that is characterized by a large-scale movement of cells, from which the embryo first begins to take shape, transitioning from a spherical mass of cells into an organized multilayered structure establishing the three primary germ layers.

Amnioserosa

An extraembryonic epithelial tissue present in Drosophila melanogaster that is required for dorsal closure.

Epiboly

Formally defined as a growing of one part over another, epiboly is a coordinated movement occurring during gastrulation that is characterized by the thinning and spreading of a multilayered cell sheet.

Radial intercalation

A tissue-rearrangement process during development in which the cells in the deep germ layers of a developing embryo move towards the outer layers.

Blastocoel

A fluid-filled cavity that the embryo develops as it forms. It is the central region of a blastocyst.

Glycocalyx

The carbohydrate-enriched coating, consisting of proteoglycans and glycoproteins, of the plasma membrane of eukaryotic, bacterial and archaeal cells. Ithas a number of functions, including roles in cell adhesion, mechanotransduction, vascular physiology, pathology, and guiding cell movement during development.

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DuFort, C., Paszek, M. & Weaver, V. Balancing forces: architectural control of mechanotransduction. Nat Rev Mol Cell Biol 12, 308–319 (2011). https://doi.org/10.1038/nrm3112

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