Actin Filament Elasticity and Retrograde Flow Shape the Force-Velocity Relation of Motile Cells

Zimmermann, J.; Brunner, Claudia; Enculescu, Mihaela; Goegler, Michael; Ehrlicher, Allen J.; Käs, Josef A.; Falcke, Martin

doi:10.1016/j.bpj.2011.12.023

Cited by 74 publications

(124 citation statements)

References 78 publications

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“…By using the equation provided by Fuerstman et al (18) [channel dimensions 6 μm wide and 3 μm high, viscosity of water 1 mPa·s, channel length 100 μm, and cell (fluid) velocity of 0.3 μm/s], we found that the net force to move this column of water was on the order of 1 pN. Usami et al, observing confined neutrophils in micropipettes (22), and others in unconfined settings (23)(24)(25), have shown that forces on the order of tens of nanonewtons are required to stall cell motion.…”

Section: Discussionmentioning

confidence: 99%

Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments

Prentice-Mott

Chang

Mahadevan

et al. 2013

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

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Cells integrate multiple measurement modalities to navigate their environment. Soluble and substrate-bound chemical gradients and physical cues have all been shown to influence cell orientation and migration. Here we investigate the role of asymmetric hydraulic pressure in directional sensing. Cells confined in microchannels identified and chose a path of lower hydraulic resistance in the absence of chemical cues. In a bifurcating channel with asymmetric hydraulic resistances, this choice was preceded by the elaboration of two leading edges with a faster extension rate along the lower resistance channel. Retraction of the "losing" edge appeared to precipitate a final choice of direction. The pressure differences altering leading edge protrusion rates were small, suggesting weak force generation by leading edges. The response to the physical asymmetry was able to override a dynamically generated chemical cue. Motile cells may use this bias as a result of hydraulic resistance, or "barotaxis," in concert with chemotaxis to navigate complex environments. Chemotactic cells, such as neutrophils and Dictyostelium, integrate chemical cues over the cell surface to move up an attractant gradient (1-5). Stiffness gradients, sensed by adhesion receptors, can also orient migration (durotaxis) (6-9). Cells must balance these and other environmental inputs to determine a direction of polarization and migration (10). Given the complex environment in tissues, it is likely that there are still unknown inputs to directional decision-making.Microfluidics provides a programmable environment for single cells in which chemical and physical cues can be precisely controlled in space and time, and polarization and migration quantified (11). In particular, cellular confinement has been instrumental in observing many novel cellular behaviors such as integrin-independent motility (12) and EGF gradient sensing (13). Additionally, cellular confinement into narrow microchannels (<10 μm) is thought to mimic the tissue environment better than stiff 2D substrates covered with low-viscosity medium.Here we use confinement to investigate the role of cell-generated hydraulic pressure in directional decisions. We show that, under strong confinement, migrating neutrophil-like cells push the column of water ahead of the cell, generating a hydraulic pressure. Cells selectively move toward a path of lower hydraulic pressure when presented with multiple paths. The morphological and signaling dynamics of this decision-making process revealed potential mechanisms that diverge from the classical PI3K-mediated chemotactic pathway. Remarkably, this physical input can outcompete conventional chemotactic signals, suggesting an important role in directing migration through tissues. ResultsTo challenge single cells with complex hydraulic environments, we used microfluidic devices that harbor bifurcating, fibronectincoated channels, derived from designs described by Ambravaneswaran et al. (14). These channels are 6 μm or smaller in width and 3 μm in height, forcing ...

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Section: Discussionmentioning

confidence: 99%

Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments

Prentice-Mott

Chang

Mahadevan

et al. 2013

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

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“…The results presented here are the continuation of the analysis of a modeling framework that has been used to explain a variety of phenomena related to actin dynamics [25], [29], [39], [40]. The derivation of the extension of the model in the form used here has been described in detail in ref.…”

Section: Introductionmentioning

confidence: 92%

Formation of Transient Lamellipodia

Zimmermann

Falcke

2014

PLoS ONE

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Cell motility driven by actin polymerization is pivotal to the development and survival of organisms and individual cells. Motile cells plated on flat substrates form membrane protrusions called lamellipodia. The protrusions repeatedly appear and retract in all directions. If a lamellipodium is stabilized and lasts for some time, it can take over the lead and determine the direction of cell motion. Protrusions traveling along the cell perimeter have also been observed. Their initiation is in some situations the effect of the dynamics of the pathway linking plasma membrane receptors to actin filament nucleation, e.g. in chemotaxis. However, lamellipodia are also formed in many cells incessantly during motion with a constant state of the signaling pathways upstream from nucleation promoting factors (NPFs), or spontaneously in resting cells. These observations strongly suggest protrusion formation can also be a consequence of the dynamics downstream from NPFs, with signaling setting the dynamic regime but not initiating the formation of individual protrusions. A quantitative mechanism for this kind of lamellipodium dynamics has not been suggested yet. Here, we present a model exhibiting excitable actin network dynamics. Individual lamellipodia form due to random supercritical filament nucleation events amplified by autocatalytic branching. They last for about 30 seconds to many minutes and are terminated by filament bundling, severing and capping. We show the relevance of the model mechanism for experimentally observed protrusion dynamics by reproducing in very good approximation the repetitive protrusion formation measured by Burnette et al. with respect to the velocities of leading edge protrusion and retrograde flow, oscillation amplitudes, periods and shape, as well as the phase relation between protrusion and retrograde flow. Our modeling results agree with the mechanism of actin bundle formation during lamellipodium retraction suggested by Burnette et al. and Koestler et al.

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“…The exponent w is positive for keratocytes, between 6 and 8, and was determined independently by aspect ratio observations and force measurements (118,152). Contrary to cell measurements, in vitro measurements and theoretical models of actin growth show a rapidly decreasing force-velocity curve, thus proving that actin dynamics alone are insufficient to explain cell measurements, and that either motor activity should be taken into account, or the length change of actin filaments under force (353). Moreover, the ability of the keratocyte cytoskeleton to return to its original shape between successive stalling experiments is striking since no effect of force or velocity change is found after the lamellipodium has been stalled, contrarily to atomic force microscopy in vitro measurements of growing actin networks (118,235).…”

Section: The Mechanics Of the Lamellipodiummentioning

confidence: 99%

Actin Dynamics, Architecture, and Mechanics in Cell Motility

Blanchoin

Boujemaa-Paterski

Sykes

et al. 2014

Physiological Reviews

1,237

1,145

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Tight coupling between biochemical and mechanical properties of the actin cytoskeleton drives a large range of cellular processes including polarity establishment, morphogenesis, and motility. This is possible because actin filaments are semi-flexible polymers that, in conjunction with the molecular motor myosin, can act as biological active springs or "dashpots" (in laymen's terms, shock absorbers or fluidizers) able to exert or resist against force in a cellular environment. To modulate their mechanical properties, actin filaments can organize into a variety of architectures generating a diversity of cellular organizations including branched or crosslinked networks in the lamellipodium, parallel bundles in filopodia, and antiparallel structures in contractile fibers. In this review we describe the feedback loop between biochemical and mechanical properties of actin organization at the molecular level in vitro, then we integrate this knowledge into our current understanding of cellular actin organization and its physiological roles. I. PREFACE ON ACTIN ORGANIZATION AND CELL MECHANICSAnimal cells (i.e., those without a cell wall) have the ability to change their shape to adapt to their environment, move through narrow spaces, divide, or allow exo-and endocytosis. The machinery of these shape changes relies on the assembly of proteins, in particular actin, a globular protein that polymerizes into filaments of different types of organization: branched and crosslinked networks, parallel bundles, and anti-parallel contractile structures (FIGURE 1A). These different architectures can be envisioned as a series of interconnected active springs and dashpots (green and red symbols in FIGURE 1B, respectively) that act as mechanical elements to drive cell shape changes and motility. The purpose of this review is to correlate recent progress in our understanding of the interplay between biochemical elements and mechanical properties. Instead of describing biochemical and mechanical properties separately, our main goal here is to address piece by piece the integrated feedback loop between biochemistry and mechanics.At the front of the cell, branched and crosslinked networks in a quasi two-dimensional sheet make up the lamellipodium, and are the major engine of cell movement since they push the cell membrane by polymerizing against it (FIGURE 1A, iii). Aligned bundles underlie filopodia that are the fingerlike structures at the front of the cell, important for directional response of the cell (FIGURE 1A, iv). A thin layer of actin, called the cell cortex, coats the plasma membrane at the back and sides of the cell, important for cell shape maintenance and changes (FIGURE 1A, i). The rest of the cell contains a three-dimensional network of crosslinked filaments interspersed with contractile bundles, including stress fibers that connect the cell cytoskeleton to the extracellular matrix via focal adhesion sites (FIGURE 1A, ii). Contraction in the cell is produced by the molecular motor protein myosin. Myosin assembles into anti...

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Actin Filament Elasticity and Retrograde Flow Shape the Force-Velocity Relation of Motile Cells

Cited by 74 publications

References 78 publications

Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments

Biased migration of confined neutrophil-like cells in asymmetric hydraulic environments

Formation of Transient Lamellipodia

Actin Dynamics, Architecture, and Mechanics in Cell Motility

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