The aim of this Review is to discuss how molecular research into the complex interplay between cell adhesion and the cytoskeleton, combined with advanced surface nanoengineering technologies, can shed light on the mechanisms by which cells sense the neighbouring microenvironment and nanoenvironment.
Cells demonstrate an extraordinary capacity to respond to a wide range of features of the surrounding matrix, including its chemical nature and physical properties.
Contemporary methods of microfabrication and nanofabrication enable the production of substrates with well-defined topography, rigidity, ligand spacing and anisotropy. Plating cells on surfaces with diverse physical properties has revealed the exquisite capacity of cells to sense, and differentially respond, to such adhesive matrices.
Mechanical modulation of the various adhesion complexes leads to the generation of integrin-mediated signals that affect multiple features of cell shape, activity and fate.
The mechanosensitivity of integrin-based adhesions (focal adhesions) is attributable to the complexity and modularity of the adhesion complexes, and their different functional modules. Specifically, mechanosensitive elements can be found in essentially every structural–functional module of the adhesion sites, including the extracellular matrix itself, the integrin receptors, the actin-linking and actin polymerization machinery, and the signal-generating and transducing modules.
Owing to the overall, combined mechanosensitivity of focal adhesions, cytoskeleton-generated forces affect the initiation, maturation and further growth of these structures.
In turn, the pre-existing integrin adhesions determine the organization of the actin cytoskeleton by creating boundary conditions that determine the spatial organization of the cytoskeleton; by inducing actin polymerization at the local level; and by global signalling, mainly through the Rho pathways, thereby regulating the overall assembly of the actin-containing structures.
Focal adhesions seem to be responsible for the spatio-temporal coordination of the multiple signalling events that are triggered by cell–extracellular matrix interactions.
Recent progress in the design and application of artificial cellular microenvironments and nanoenvironments has revealed the extraordinary ability of cells to adjust their cytoskeletal organization, and hence their shape and motility, to minute changes in their immediate surroundings. Integrin-based adhesion complexes, which are tightly associated with the actin cytoskeleton, comprise the cellular machinery that recognizes not only the biochemical diversity of the extracellular neighbourhood, but also its physical and topographical characteristics, such as pliability, dimensionality and ligand spacing. Here, we discuss the mechanisms of such environmental sensing, based on the finely tuned crosstalk between the assembly of one type of integrin-based adhesion complex, namely focal adhesions, and the forces that are at work in the associated cytoskeletal network owing to actin polymerization and actomyosin contraction.
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The authors are grateful to K. Yamada for providing the photographs for FIG. 1 and to B. Morgenstern for expert help in preparing this article for publication. The authors' work was partially supported by the Volkswagen Foundation, the National Institutes of Health (NIH; through the NIH Roadmap for Medical Research), the Israel Science Foundation, the Minerva Foundation, the Maurice Janin Fund and the Landesstiftung Baden-Württemberg. B.G. holds the Erwin Neter Professorial Chair in Cell and Tumour Biology. A.D.B. holds the Joseph Moss Professorial Chair in Biomedical Research. J.P.S. is a Weston Visiting Professor at the Weizmann Institute of Science.
- Extracellular matrix
(ECM). The complex, multimolecular material that surrounds cells. The ECM comprises a scaffold on which tissues are organized, provides cellular microenvironments and regulates multiple cellular functions.
- Focal adhesion
An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin-signalling platform.
- Focal complex
A small (1 μm diameter), dot-like adhesion structure that is formed underneath the lamellipodium.
A ribbon-like, flat protrusion at the periphery of a moving or spreading cell that is enriched with a branched network of actin filaments.
A flat, sheet-like extension that is found at the cell periphery but is more internal than lamellipodia. A fan-shaped lamella is a prominent feature that characterizes the leading edge of a cell that is undergoing locomotion on a flat surface. Actin networks, also containing myosin IIA, are the principal structures in lamellae.
A thin, transient actin protrusion that extends out from the cell surface and is formed by the elongation of bundled actin filaments in its core.
- LIM domain
A repeat of ∼60 amino acids that contains Cys and His residues. The LIM domain is thought to be involved in protein–protein interactions.
- Stress fibres
Also termed actin-microfilament bundles, these are arrays of parallel filaments that contain filamentous actin and myosin II, and often stretch between cell attachments as if under stress.
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Geiger, B., Spatz, J. & Bershadsky, A. Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10, 21–33 (2009). https://doi.org/10.1038/nrm2593
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