Spatiotemporal Constraints on the Force-Dependent Growth of Focal Adhesions

Stricker, Jonathan; Aratyn-Schaus, Yvonne; Oakes, Patrick W.; Gardel, Margaret L.

doi:10.1016/j.bpj.2011.05.023

Cited by 187 publications

(224 citation statements)

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“…S2. Furthermore, such assemblies are mostly distributed at the cell periphery (18,19), as shown in Fig. 1A.…”

Section: Methodsmentioning

confidence: 93%

“…The FA band is treated as an elastic plaque representing the stiffness of the constituent molecules (with Young's modulus E p ) connected to the ECM through an array of integrins (modeled as springs with stiffness k i ) whose density (ϕ i ) is assumed to be proportional to the fiber density (ϕ f ) underneath the cell. Although more complicated models with strain-dependent detachment rates can be used for integrins, recent experiments have shown that a simple description (i.e., treating the integrin as a linear spring) can capture the response of integrins sufficiently because the timescale for integrin binding dynamics [i.e., a few seconds (9,20)] is much shorter than that for FA growth [i.e., a few minutes (18)]. In addition, the proximal end of the band is connected to the cell nucleus through stress fibers (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Given that integrin binding/unbinding occurs within seconds (9,20), whereas the assembly of proteins in the FA takes several minutes (18), the growth of FA should primarily depend on how fast adhesion proteins are added/removed from the plaque. Furthermore, as suggested by experiments, we proceed by assuming that protein recruitment/disassembly can only take place at the edge of the FA plaque (21).…”

Section: Methodsmentioning

confidence: 99%

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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.

100

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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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“…S2. Furthermore, such assemblies are mostly distributed at the cell periphery (18,19), as shown in Fig. 1A.…”

Section: Methodsmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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.

100

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“…Moreover, recent modeling (18) as well as indirect observations (19,20) suggest that the contractile actomyosin apparatus can act as a global rigidity sensor (21). From a physical point of view, the deformation of the surrounding matrix in response to cell contractility is poorly understood; plausible mechanisms of cell mechanosensitivity imply that the regulation could be either mediated by the stress exerted by cells, or by the strain in the ECM (7,(22)(23)(24). These intriguing questions are currently intensively debated, because the detailed mechanisms of force transduction in response to ECM might explain the observed discrepancies in adhesion (1, 25), migration (2, 26), and differentiation (3, 27) of cells in environments of different rigidities and over different time scales.…”

mentioning

confidence: 99%

Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness

Trichet

Digabel

Hawkins

et al. 2012

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

513

521

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Cell migration plays a major role in many fundamental biological processes, such as morphogenesis, tumor metastasis, and wound healing. As they anchor and pull on their surroundings, adhering cells actively probe the stiffness of their environment. Current understanding is that traction forces exerted by cells arise mainly at mechanotransduction sites, called focal adhesions, whose size seems to be correlated to the force exerted by cells on their underlying substrate, at least during their initial stages. In fact, our data show by direct measurements that the buildup of traction forces is faster for larger substrate stiffness, and that the stress measured at adhesion sites depends on substrate rigidity. Our results, backed by a phenomenological model based on active gel theory, suggest that rigidity-sensing is mediated by a large-scale mechanism originating in the cytoskeleton instead of a local one. We show that large-scale mechanosensing leads to an adaptative response of cell migration to stiffness gradients. In response to a step boundary in rigidity, we observe not only that cells migrate preferentially toward stiffer substrates, but also that this response is optimal in a narrow range of rigidities. Taken together, these findings lead to unique insights into the regulation of cell response to external mechanical cues and provide evidence for a cytoskeleton-based rigidity-sensing mechanism.actin cytoskeleton | microfabrication | mechanobiology | cell mechanics C ell migration is not only sensitive to the biochemical composition of the environment, but also to its mechanical properties. Cells directly probe the physical properties of their environment, such as substrate stiffness, by pulling on it. Increasing evidence show that matrix or tissue elasticity has a key role in regulating numerous cell functions, such as adhesion (1), migration (2) and differentiation (3). Such functions are affected by cell-generated actomyosin forces that depend on substrate stiffness through a feedback mechanism (4). The sensitivity of cells to mechanical properties of the extracellular matrix (ECM) arises from the mechanosensitive nature of cell adhesion. Numerous plausible candidates for the transduction of mechanochemical signals have been tested (5). Among them, focal adhesions (FAs) appear to be the most prominent, as shown by the reported correlation between their area and sustained force exhibiting a constant stress (6-9). This mechanosensitivity is usually accounted for by a generic local mechanism in which a force applied to an FA induces an elastic deformation of the contact that triggers conformational and organizational changes of some of its constitutive proteins, which in turn can enhance binding with new proteins enabling growth of the contact (10-12). However, how this local mechanosensitivity can result in the ability of cells to sense and respond to the rigidity of their surroundings (2, 3, 13, 14) at a large scale remains largely unknown (5, 15). Much conflicting evidence has emerged from a variety of studi...

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“…This, in concert with focal adhesion kinase (FAK), Src and other signalling modules controlled via integrin ligation, directs focal adhesion (FA) assembly and maturation 19 . Importantly, such assembly processes are regulated by mechanical force [20][21][22] . In particular, nascent complexes, including scaffolding molecules such as paxillin (Pxn), form at the leading edge, while myosin II-mediated tension leads to recruitment and activation of accessory proteins, promoting growth of the complex distal to the leading edge 23 .…”

mentioning

confidence: 99%

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Fiore

Chen

et al. 2014

Nat Commun

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Cancer cell adhesion to the vascular endothelium is a critical step of tumour metastasis. Endothelial surface molecule Thy-1 (CD90) is implicated in the metastatic process through its interactions with integrins and syndecans. However, how Thy-1 supports cell-cell adhesion in a dynamic mechanical environment is not known. Here we show that Thy-1 supports b 1 integrin-and syndecan-4 (Syn4)-mediated contractility-dependent mechanosignalling of melanoma cells. At the single-molecule level, Thy-1 is capable of independently binding a 5 b 1 integrin and syndecan-4 (Syn4) receptors. However, in the presence of both a 5 b 1 and Syn4, the two receptors bind cooperatively to Thy-1, to form a trimolecular complex. This trimolecular complex displays a unique phenomenon we coin 'dynamic catch', characterized by abrupt bond stiffening followed by the formation of catch bonds, where force prolongs the bond lifetime. Thus, we reveal a new class of trimolecular interactions where force strengthens the synergistic binding of two co-receptors and modulates downstream mechanosignalling.

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Spatiotemporal Constraints on the Force-Dependent Growth of Focal Adhesions

Cited by 187 publications

References 50 publications

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

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

Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

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