Cell mechanosensitivity controls the anisotropy of focal adhesions

Nicolas, Alice; Geiger, Benjamin; Safran, S. A.

doi:10.1073/pnas.0403539101

Cited by 211 publications

(237 citation statements)

References 25 publications

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“…It has been suggested that forces transmitted to the cytoskeleton may result in deformations of the cell membrane and mechanical opening of transmembrane ion channels, 35 as well as elastic deformation of the focal adhesion complex. 36 In this process extracellular cues are transduced through the actin and microtubule cytoskeleton to effect changes in morphology, motility and forward advance. 37 Certainly, FXs are associated with high motility and FBs are associated with a lack of motility.…”

Section: Discussionmentioning

confidence: 99%

Regulation of implant surface cell adhesion: characterization and quantification of S‐phase primary osteoblast adhesions on biomimetic nanoscale substrates

Biggs

Richards

Gadegaard

et al. 2006

Journal Orthopaedic Research

109

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Integration of an orthopedic prosthesis for bone repair must be associated with osseointegration and implant fixation, an ideal that can be approached via topographical modification of the implant/bone interface. It is thought that osteoblasts use cellular extensions to gather spatial information of the topographical surroundings prior to adhesion formation and cellular flattening. Focal adhesions (FAs) are dynamic structures associated with the actin cytoskeleton that form adhesion plaques of clustered integrin receptors that function in coupling the cell cytoskeleton to the extracellular matrix (ECM). FAs contain structural and signalling molecules crucial to cell adhesion and survival. To investigate the effects of ordered nanotopographies on osteoblast adhesion formation, primary human osteoblasts (HOBs) were cultured on experimental substrates possessing a defined array of nanoscale pits. Nickel shims of controlled nanopit dimension and configuration were fabricated by electron beam lithography and transferred to polycarbonate (PC) discs via injection molding. Nanopits measuring 120 nm diameter and 100 nm in depth with 300 nm center-center spacing were fabricated in three unique geometric conformations: square, hexagonal, and near-square (300 nm spaced pits in square pattern, but with AE50 nm disorder). Immunofluorescent labeling of vinculin allowed HOB adhesion complexes to be visualized and quantified by image software. Perhipheral adhesions as well as those within the perinuclear region were observed, and adhesion length and number were seen to vary on nanopit substrates relative to smooth PC. S-phase cells on experimental substrates were identified with bromodeoxyuridine (BrdU) immunofluorescent detection, allowing adhesion quantification to be conducted on a uniform flattened population of cells within the S-phase of the cell cycle. Findings of this study demonstrate the disruptive effects of ordered nanopits on adhesion formation and the role the conformation of nanofeatures plays in modulating these effects. Highly ordered arrays of nanopits resulted in decreased adhesion formation and a reduction in adhesion length, while introducing a degree of controlled disorder present in near-square arrays, was shown to increase focal adhesion formation and size. HOBs were also shown to be affected morphologicaly by the presence and conformation of nanopits. Ordered arrays affected cellular spreading, and induced an elongated cellular phenotype, indicative of increased motility, while near-square nanopit symmetries induced HOB spreading. It is postulated that nanopits affect osteoblast-substrate adhesion by directly or indirectly affecting adhesion complex formation, a phenomenon dependent on nanopit dimension and conformation. ß

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Section: Discussionmentioning

confidence: 99%

Regulation of implant surface cell adhesion: characterization and quantification of S‐phase primary osteoblast adhesions on biomimetic nanoscale substrates

Biggs

Richards

Gadegaard

et al. 2006

Journal Orthopaedic Research

109

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“…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). Finally, the driving force for growth of the plaque is assumed to be the chemical potential difference between plaque units recruited to the plaque and those in the cytosol.…”

Section: Methodsmentioning

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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“…This has been studied extensively in the context of cellular responses to increased ECM rigidity, which showed that integrin adhesions grow in size and are strengthened by local assembly of the actin cytoskeleton and activation of actomyosin contraction (17)(18)(19). These mechanical cues have physiological consequences, as ECM rigidity influences stem cell fate and cell differentiation (20).…”

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confidence: 99%

Changes in E-cadherin rigidity sensing regulate cell adhesion

Collins

Denisin

Pruitt

et al. 2017

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

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Mechanical cues are sensed and transduced by cell adhesion complexes to regulate diverse cell behaviors. Extracellular matrix (ECM) rigidity sensing by integrin adhesions has been well studied, but rigidity sensing by cadherins during cell adhesion is largely unexplored. Using mechanically tunable polyacrylamide (PA) gels functionalized with the extracellular domain of E-cadherin (Ecad-Fc), we showed that E-cadherin-dependent epithelial cell adhesion was sensitive to changes in PA gel elastic modulus that produced striking differences in cell morphology, actin organization, and membrane dynamics. Traction force microscopy (TFM) revealed that cells produced the greatest tractions at the cell periphery, where distinct types of actin-based membrane protrusions formed. Cells responded to substrate rigidity by reorganizing the distribution and size of hightraction-stress regions at the cell periphery. Differences in adhesion and protrusion dynamics were mediated by balancing the activities of specific signaling molecules. Cell adhesion to a 30-kPa Ecad-Fc PA gel required Cdc42-and formin-dependent filopodia formation, whereas adhesion to a 60-kPa Ecad-Fc PA gel induced Arp2/3-dependent lamellipodial protrusions. A quantitative 3D cell-cell adhesion assay and live cell imaging of cell-cell contact formation revealed that inhibition of Cdc42, formin, and Arp2/3 activities blocked the initiation, but not the maintenance of established cell-cell adhesions. These results indicate that the same signaling molecules activated by E-cadherin rigidity sensing on PA gels contribute to actin organization and membrane dynamics during cell-cell adhesion. We hypothesize that a transition in the stiffness of E-cadherin homotypic interactions regulates actin and membrane dynamics during initial stages of cellcell adhesion.C ell adhesion is essential for tissue structure and function. Cells use specialized types of adhesions to interact with the surrounding environment, including integrin-based focal adhesions at cell-extracellular matrix (cell-ECM) contacts and cadherin-based adhesions at cell-cell contacts (1). Integrins bind to the ECM and intracellular proteins that link to the actin cytoskeleton and important signaling pathways (2). Similarly, cadherins regulate cellcell recognition and adhesion (3) and, through cytoplasmic adaptor proteins (catenins, vinculin) (4, 5), also link to the actin cytoskeleton and other proteins with signaling and scaffolding functions (6).Initiation of cell-cell adhesion requires significant reorganization of the actin cytoskeleton and is tightly controlled by the activities of actin nucleating proteins and Rho GTPases. Adhesion is initiated when filopodia from opposing cells come into contact with one another (7,8), and this process is regulated by Cdc42 activity (9, 10) and formin-dependent actin polymerization (11)(12)(13)(14). Intermediate stages of cell-cell contact formation involve lateral expansion of the contact by Rac1-induced and Arp2/3-dependent lamellipodial activity (15, 16). Finally, com...

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Cell mechanosensitivity controls the anisotropy of focal adhesions

Cited by 211 publications

References 25 publications

Regulation of implant surface cell adhesion: characterization and quantification of S‐phase primary osteoblast adhesions on biomimetic nanoscale substrates

Regulation of implant surface cell adhesion: characterization and quantification of S‐phase primary osteoblast adhesions on biomimetic nanoscale substrates

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

Changes in E-cadherin rigidity sensing regulate cell adhesion

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