Traction stress analysis and modeling reveal that amoeboid migration in confined spaces is accompanied by expansive forces and requires the structural integrity of the membrane–cortex interactions

Yip, Ai Kia; Chiam, Keng-Hwee; Matsudaira, Paul

doi:10.1039/c4ib00245h

Cited by 40 publications

(56 citation statements)

References 72 publications

(192 reference statements)

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“…5D). Our observations that WAVE-null cells polarize and migrate using blebs are consistent with prior work showing that neutrophils and other migratory cells use distinct strategies to achieve migration in different external environments (Bergert et al, 2012;Liu et al, 2015b;Noselli et al, 2019;Wilson et al, 2013;Yip et al, 2015). However, neutrophils migrating using this bleb-based mode strongly polarize Rac activity to a small section of the plasma membrane ( Fig.…”

Section: Discussionsupporting

confidence: 91%

Cell confinement reveals a branched-actin independent circuit for neutrophil polarity

Graziano¹,

Town²,

Nagy³

et al. 2018

Preprint

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Migratory cells use distinct motility modes to navigate different microenvironments, but it is unclear whether these modes rely on the same core set of polarity components. To investigate this, we disrupted Arp2/3 and WAVE complex, which assemble branched actin networks that are essential for neutrophil polarity and motility in standard adherent conditions. Surprisingly, confinement rescues polarity and movement of neutrophils lacking these components, revealing a processive bleb-based protrusion program that is mechanistically distinct from the branched actin-based protrusion program but shares some of the same core components and underlying molecular logic. We further find that the restriction of protrusion growth to one site does not always respond to membrane tension directly, as previously thought, but may rely on closely linked properties such as local membrane curvature. Our work reveals a hidden circuit for neutrophil polarity and indicates that cells have distinct molecular mechanisms for polarization that dominate in different microenvironments.to produce a single protrusion ( Fig. 1A) (Diz-Muñoz et al., 2016;Houk et al., 2012;Keren et al., 2008;Sens and Plastino, 2015).While actin polymerization serves as a key ingredient in generating the positive and negative feedback loops that give rise to polarity, we lack an understanding of how specific types of actin networks provide each kind of feedback. Immune cells assemble multiple actin networks at different subcellular locations that carry out distinct functions to support migration: Arp2/3dependent assembly of branched actin networks at the leading edge contributes to cell guidance/steering and protrusion extension, while actomyosin bundles near the trailing edge provide contractile force to lift the cell rear and squeeze the cell body forward (Lämmermann and Germain, 2014;Moreau et al., 2018). Along with these functional differences, the types of actin networks immune cells and other migratory cells employ for migration vary with microenvironment (Lämmermann and Germain, 2014;Paluch et al., 2016). The role of actin dynamics in migration is complex and likely depends on the type of actin network, its subcellular location, and the extracellular environment. Existing tools to probe the role of actin networks in both the positive and negative feedback loops needed for polarity are fairly crude and have largely been based on pharmacological perturbations that target all actin polymer (Diz-Muñoz et al., 2016;Huang et al., 2013;Inoue and Meyer, 2008;Sasaki et al., 2007;Wang et al., 2002;Weiner et al., 2007;Yang et al., 2016). More surgical experiments are needed to clarify how different subcellular actin networks contribute to polarity generation under different environmental conditions. Figure 1. WAVE complex is required for neutrophil polarity and motility.A) Polarity generation depends on fast-acting, short-range positive feedback and slower-acting, long-range negative feedback. Actin assembly participates in both types of feedback, with its role in negat...

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Section: Discussionsupporting

confidence: 91%

Cell confinement reveals a branched-actin independent circuit for neutrophil polarity

Graziano¹,

Town²,

Nagy³

et al. 2018

Preprint

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“…The advantage of our model is that we are able to isolate and study intracellular pressure dynamics, which cannot be isolated in vivo. Other models of blebbing cells have ignored the poroelasticity of the cytoplasm (5,13,16,(20)(21)(22), which could limit our understanding of pressure-driven protrusions in migrating cells.…”

Section: Biophysical Journal 110(5) 1168-1179mentioning

confidence: 99%

“…Blebs are spherical membrane protrusions characterized by a separation of the cell membrane from the actin cytoskeleton (1), and have been observed as leading-edge protrusions during cell migration over flat surfaces (2)(3)(4), in confined channels (5), and in three-dimensional (3D) environments (6,7). Bleb expansion is driven by intracellular pressure generated by contractile stresses acting on the cytoskeleton.…”

Section: Introductionmentioning

confidence: 99%

“…Although this model took into account blebbing dynamics, the driving pressure was assumed to be uniform in space, and is not appropriate for investigating questions relating to cytoplasmic rheology. Several recent models that take into account bleb dynamics with cytoplasmic flow have been developed and used to explore cell migration in a confined channel (5,19), circus blebbing (20), and bleb expansion (21,22). All of these models treated the cytoplasm as a viscous fluid, and would need to be extended to model more complex cytoplasmic rheology.…”

Section: Introductionmentioning

confidence: 99%

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Intracellular Pressure Dynamics in Blebbing Cells

Strychalski

Guy

2016

Biophysical Journal

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Blebs are pressure-driven protrusions that play an important role in cell migration, particularly in three-dimensional environments. A bleb is initiated when the cytoskeleton detaches from the cell membrane, resulting in the pressure-driven flow of cytosol toward the area of detachment and local expansion of the cell membrane. Recent experiments involving blebbing cells have led to conflicting hypotheses regarding the timescale of intracellular pressure propagation. The interpretation of one set of experiments supports a poroelastic model of the cytoplasm that leads to slow pressure equilibration when compared to the timescale of bleb expansion. A different study concludes that pressure equilibrates faster than the timescale of bleb expansion. To address this discrepancy, a dynamic computational model of the cell was developed that includes mechanics of and the interactions among the cytoplasm, the actin cortex, the cell membrane, and the cytoskeleton. The model results quantify the relationship among cytoplasmic rheology, pressure, and bleb expansion dynamics, and provide a more detailed picture of intracellular pressure dynamics. This study shows the elastic response of the cytoplasm relieves pressure and limits bleb size, and that both permeability and elasticity of the cytoplasm determine bleb expansion time. Our model with a poroelastic cytoplasm shows that pressure disturbances from bleb initiation propagate faster than the timescale of bleb expansion and that pressure equilibrates slower than the timescale of bleb expansion. The multiple timescales in intracellular pressure dynamics explain the apparent discrepancy in the interpretation of experimental results.

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“…The assumption that forces on the cortex are not equilibrated may be valid during highly dynamic processes such as during cell migration [41]. However, some experiments involve isolating a specific event, such as the expansion of a single bleb in [34].…”

Section: Cellular Blebbingmentioning

confidence: 99%

2D force constraints in the method of regularized Stokeslets

Maxian¹,

Strychalski²

2019

Commun. Appl. Math. Comput. Sci.

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For many biological systems that involve elastic structures immersed in fluid, small length scales mean that inertial effects are also small, and the fluid obeys the Stokes equations. One way to solve the model equations representing such systems is through the Stokeslet, the fundamental solution to the Stokes equations, and its regularized counterpart, which treats the singularity of the velocity at points where force is applied. In two dimensions, an additional complication arises from Stokes' paradox, whereby the velocity from the Stokeslet is unbounded at infinity when the net hydrodynamic force within the domain is nonzero, invalidating any solutions that use the free space Stokeslet. A straightforward computationally inexpensive method is presented for obtaining valid solutions to the Stokes equations for net nonzero forcing. The approach is based on modifying the boundary conditions of the Stokes equations to impose a mean zero velocity condition on a large curve that surrounds the domain of interest. The corresponding Green's function is derived and used as a fundamental solution in the case of net nonzero forcing. The numerical method is applied to models of cellular motility and blebbing, both of which involve tether forces that are not required to integrate to zero.

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Traction stress analysis and modeling reveal that amoeboid migration in confined spaces is accompanied by expansive forces and requires the structural integrity of the membrane–cortex interactions

Cited by 40 publications

References 72 publications

Cell confinement reveals a branched-actin independent circuit for neutrophil polarity

Cell confinement reveals a branched-actin independent circuit for neutrophil polarity

Intracellular Pressure Dynamics in Blebbing Cells

2D force constraints in the method of regularized Stokeslets

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