Probing mechanical principles of focal contacts in cell–matrix adhesion with a coupled stochastic–elastic modelling framework

Gao, Huajian; Qian, Jin; Chen, Bin

doi:10.1098/rsif.2011.0157

Cited by 90 publications

(78 citation statements)

References 92 publications

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“…Although it is difficult to demonstrate experimentally owing to limited spatial resolution, force distribution in an elastic system is unlikely to be homogeneous. Theoretical models predict that, as adhesion size increases or substrate stiffness decreases, force localizes more and more strongly to the adhesion rim, eventually leading to a crack-like failure of the adhesion site (Qian et al, 2009;Gao et al, 2011). Such a mechanism would also work for apparent catch bonds, as they always become slip bonds at sufficiently high forces.…”

Section: Limits Of Physical Stability and Mechanosensitive Responsesmentioning

confidence: 99%

United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction

Schwarz

Gardel

2012

Journal of Cell Science

307

317

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SummaryMany essential cellular functions in health and disease are closely linked to the ability of cells to respond to mechanical forces. In the context of cell adhesion to the extracellular matrix, the forces that are generated within the actin cytoskeleton and transmitted through integrin-based focal adhesions are essential for the cellular response to environmental clues, such as the spatial distribution of adhesive ligands or matrix stiffness. Whereas substantial progress has been made in identifying mechanosensitive molecules that can transduce mechanical force into biochemical signals, much less is known about the nature of cytoskeletal force generation and transmission that regulates the magnitude, duration and spatial distribution of forces imposed on these mechanosensitive complexes. By focusing on cellmatrix adhesion to flat elastic substrates, on which traction forces can be measured with high temporal and spatial resolution, we discuss our current understanding of the physical mechanisms that integrate a large range of molecular mechanotransduction events on cellular scales. Physical limits of stability emerge as one important element of the cellular response that complements the structural changes affected by regulatory systems in response to mechanical processes.

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Section: Limits Of Physical Stability and Mechanosensitive Responsesmentioning

confidence: 99%

United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction

Schwarz

Gardel

2012

Journal of Cell Science

307

317

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“…In particular, in vitro studies using elastic hydrogels have shown that forces generated by actomyosin contraction are essential for the stabilization of FAs (5,6). Numerous observations have convincingly demonstrated that cells form larger FAs as well as develop higher intracellular traction forces on stiffer ECMs (7,8), evidencing the mechanosensitive nature of FAs which has been quantitatively modeled using different (continuum, coarse-grain, and molecular) approaches (9,10).…”

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confidence: 99%

Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

Cao

Ban

Baker

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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We describe a multiscale model that incorporates force-dependent mechanical plasticity induced by interfiber cross-link breakage and stiffness-dependent cellular contractility to predict focal adhesion (FA) growth and mechanosensing in fibrous extracellular matrices (ECMs). The model predicts that FA size depends on both the stiffness of ECM and the density of ligands available to form adhesions. Although these two quantities are independent in commonly used hydrogels, contractile cells break cross-links in soft fibrous matrices leading to recruitment of fibers, which increases the ligand density in the vicinity of cells. Consequently, although the size of focal adhesions increases with ECM stiffness in nonfibrous and elastic hydrogels, plasticity of fibrous networks leads to a departure from the well-described positive correlation between stiffness and FA size. We predict a phase diagram that describes nonmonotonic behavior of FA in the space spanned by ECM stiffness and recruitment index, which describes the ability of cells to break cross-links and recruit fibers. The predicted decrease in FA size with increasing ECM stiffness is in excellent agreement with recent observations of cell spreading on electrospun fiber networks with tunable cross-link strengths and mechanics. Our model provides a framework to analyze cell mechanosensing in nonlinear and inelastic ECMs.focal adhesion | mechanosensing | cell contractility | matrix physical remodeling | Rho pathway F ocal adhesions (FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and cells. FAs play important roles in many cellular behaviors, including proliferation, differentiation, and locomotion, and pathological processes like tumorigenesis and wound healing (1-4). For this reason, intense efforts have been devoted to understanding how key signaling molecules and ECM characteristics influence the formation and growth of FAs. In particular, in vitro studies using elastic hydrogels have shown that forces generated by actomyosin contraction are essential for the stabilization of FAs (5, 6). Numerous observations have convincingly demonstrated that cells form larger FAs as well as develop higher intracellular traction forces on stiffer ECMs (7,8), evidencing the mechanosensitive nature of FAs which has been quantitatively modeled using different (continuum, coarse-grain, and molecular) approaches (9, 10).It must be pointed out that in all of the aforementioned investigations, the substrates considered were flat (2D) and linear elastic. However, in vivo, many cells reside within 3D fibrous scaffolds where the density and diameter of fibers can vary depending on the nature of the tissue (11-13). The local architecture of these fibrous networks may change significantly when cells exert forces on them, leading to phenomena such as nonlinear stiffening, reorientation, and physical remodeling of the ECM (14, 15). Our recent study on cells in synthetic fibrous matrices wit...

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“…Simulations of the mechanical cues that regulate cellular processes have demonstrated the dynamic nature of the mechanical strength of focal adhesions, and that the cell can actively change these to alter its migration velocity (Wong and Tang, 2011). However, there are still knowledge gaps with regards to how mechanical forces can influence intracellular processes (Gao et al, 2011;Kim et al, 2011 Fig. 2.…”

Section: Box 2 Continuum Discrete and Hybrid Mathematical Modellingmentioning

confidence: 99%

A multiscale road map of cancer spheroids – incorporating experimental and mathematical modelling to understand cancer progression

Loessner

Little

Pettet

et al. 2013

Journal of Cell Science

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SummaryComputational models represent a highly suitable framework, not only for testing biological hypotheses and generating new ones but also for optimising experimental strategies. As one surveys the literature devoted to cancer modelling, it is obvious that immense progress has been made in applying simulation techniques to the study of cancer biology, although the full impact has yet to be realised. For example, there are excellent models to describe cancer incidence rates or factors for early disease detection, but these predictions are unable to explain the functional and molecular changes that are associated with tumour progression. In addition, it is crucial that interactions between mechanical effects, and intracellular and intercellular signalling are incorporated in order to understand cancer growth, its interaction with the extracellular microenvironment and invasion of secondary sites. There is a compelling need to tailor new, physiologically relevant in silico models that are specialised for particular types of cancer, such as ovarian cancer owing to its unique route of metastasis, which are capable of investigating anti-cancer therapies, and generating both qualitative and quantitative predictions. This Commentary will focus on how computational simulation approaches can advance our understanding of ovarian cancer progression and treatment, in particular, with the help of multicellular cancer spheroids, and thus, can inform biological hypothesis and experimental design.

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Probing mechanical principles of focal contacts in cell–matrix adhesion with a coupled stochastic–elastic modelling framework

Cited by 90 publications

References 92 publications

United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction

United we stand – integrating the actin cytoskeleton and cell–matrix adhesions in cellular mechanotransduction

Multiscale model predicts increasing focal adhesion size with decreasing stiffness in fibrous matrices

A multiscale road map of cancer spheroids – incorporating experimental and mathematical modelling to understand cancer progression

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