Morphology of the Lamellipodium and Organization of Actin Filaments at the Leading Edge of Crawling Cells

Atılgan, Erdinç; Wirtz, Denis; Sun, Sean X.

doi:10.1529/biophysj.105.065383

Cited by 89 publications

(98 citation statements)

References 72 publications

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“…Recent advances in multiple particle-tracking rheology (23,24) as well as the use of nested collagen matrices (25,26) to probe tension in the proximity of cells have shown great promise in improving our understanding of cell-matrix interactions at these length scales.…”

Section: Resultsmentioning

confidence: 99%

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Zaman

Trapani

Sieminski

et al. 2006

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

1,061

1,005

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Cell migration on 2D surfaces is governed by a balance between counteracting tractile and adhesion forces. Although biochemical factors such as adhesion receptor and ligand concentration and binding, signaling through cell adhesion complexes, and cytoskeletal structure assembly/disassembly have been studied in detail in a 2D context, the critical biochemical and biophysical parameters that affect cell migration in 3D matrices have not been quantitatively investigated. We demonstrate that, in addition to adhesion and tractile forces, matrix stiffness is a key factor that influences cell movement in 3D. Cell migration assays in which Matrigel density, fibronectin concentration, and β1 integrin binding are systematically varied show that at a specific Matrigel density the migration speed of DU-145 human prostate carcinoma cells is a balance between tractile and adhesion forces. However, when biochemical parameters such as matrix ligand and cell integrin receptor levels are held constant, maximal cell movement shifts to matrices exhibiting lesser stiffness. This behavior contradicts current 2D models but is predicted by a recent force-based computational model of cell movement in a 3D matrix. As expected, this 3D motility through an extracellular environment of pore size much smaller than cellular dimensions does depend on proteolytic activity as broad-spectrum matrix metalloproteinase (MMP) inhibitors limit the migration of DU-145 cells and also HT-1080 fibrosarcoma cells. Our experimental findings here represent, to our knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments.

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Section: Resultsmentioning

confidence: 99%

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Zaman

Trapani

Sieminski

et al. 2006

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

1,061

1,005

View full text Add to dashboard Cite

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“…However, even in very dynamic systems like the leading edges of migrating cells, the spatial location of Arp2/3 must be highly restricted to maintain typical actin treadmilling (Svitkina and Borisy, 1999;Atilgan et al, 2005;Shao et al, 2006). Therefore, the restricted spatial organization within the spinoplasm seen here likely represents the focus of activity of the Arp2/3 complex.…”

Section: Methodological Constraintsmentioning

confidence: 88%

Organization of the Arp2/3 Complex in Hippocampal Spines

Rácz¹,

Weinberg²

2008

J. Neurosci.

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Changes in the morphology of a dendritic spine require remodeling of its actin-based cytoskeleton. Biochemical mechanisms underlying actin remodeling have been studied extensively, but little is known about the physical organization of the actin-binding proteins that mediate remodeling in spines. Long-term potentiation-inducing stimuli trigger expansion of the spine head, suggesting local extension and branching of actin filaments. Because filament branching requires the Arp2/3 complex, we used quantitative immunoelectron microscopy to elucidate the organization of ARPC-2 (Arp2/3 complex subunit 2), an essential component of the complex. Our data from CA1 hippocampus indicate that Arp2/3 concentrates within spines in a previously unrecognized torroidal domain, apparently specialized to mediate actin filament branching.

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“…Instead, they are constantly extending and retracting protrusions (lamellipodia, large sheetlike protrusions, and filopodia, thin finger-like protrusions) (5)(6)(7)(8).…”

mentioning

confidence: 99%

A mechanical model of actin stress fiber formation and substrate elasticity sensing in adherent cells

Walcott

Sun²

2010

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

Self Cite

214

161

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Tissue cells sense and respond to the stiffness of the surface on which they adhere. Precisely how cells sense surface stiffness remains an open question, though various biochemical pathways are critical for a proper stiffness response. Here, based on a simple mechanochemical model of biological friction, we propose a model for cell mechanosensation as opposed to previous more biochemically based models. Our model of adhesion complexes predicts that these cell-surface interactions provide a viscous drag that increases with the elastic modulus of the surface. The force-velocity relation of myosin II implies that myosin generates greater force when the adhesion complexes slide slowly. Then, using a simple cytoskeleton model, we show that an external force applied to the cytoskeleton causes actin filaments to aggregate and orient parallel to the direction of force application. The greater the external force, the faster this aggregation occurs. As the steady-state probability of forming these bundles reflects a balance between the time scale of bundle formation and destruction (because of actin turnover), more bundles are formed when the cytoskeleton time-scale is small (i.e., on stiff surfaces), in agreement with experiment. As these large bundles of actin, called stress fibers, appear preferentially on stiff surfaces, our mechanical model provides a mechanism for stress fiber formation and stiffness sensing in cells adhered to a compliant surface.biological friction | cell biomechanics | cytoskeleton | focal adhesions | mechanosensitivity A ll cells sense and respond to their environment. A prototypical example is chemical sensing mediated by cell-surface receptors, e.g., a neuron cell can sense small changes in external neural transmitter concentration and responds by opening ion channels and changing internal membrane polarization. A different kind of sensing has been receiving attention lately where some cells directly respond to mechanical properties of their environment, such as the stiffness of the surface to which they adhere. Understanding how these cells sense and respond to their mechanical environment and how they are able to translate mechanical cues into a chemical response are both topics of great interest in cell biomechanics.Here, we are motivated by how stem cells sense and respond to their local mechanical environment. Viability of mesenchymal stem cells depends on their adherence to a surface. Interestingly, the differentiation of these cells is dependent on substrate stiffness. For example, stem cells on soft surfaces become primarily brain cells; on intermediate surfaces they become muscle cells and on stiff surfaces they become bone (1). Precisely how these cells sense surface stiffness, and how surface mechanics leads to the underlying biochemical changes that determine cell identity are still open questions (2). Several processes are thought to be involved. In particular, adhesion complexes (ACs), nonmuscle myosin II, and stress fibers are all thought to play a role. In fact, it seems likel...

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Morphology of the Lamellipodium and Organization of Actin Filaments at the Leading Edge of Crawling Cells

Cited by 89 publications

References 72 publications

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Organization of the Arp2/3 Complex in Hippocampal Spines

A mechanical model of actin stress fiber formation and substrate elasticity sensing in adherent cells

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