Dataset Information

Coupling actin flow, adhesion, and morphology in a computational cell motility model.

ABSTRACT: Cell migration is a pervasive process in many biology systems and involves protrusive forces generated by actin polymerization, myosin dependent contractile forces, and force transmission between the cell and the substrate through adhesion sites. Here we develop a computational model for cell motion that uses the phase-field method to solve for the moving boundary with physical membrane properties. It includes a reaction-diffusion model for the actin-myosin machinery and discrete adhesion sites which can be in a "gripping" or "slipping" mode and integrates the adhesion dynamics with the dynamics of the actin filaments, modeled as a viscous network. To test this model, we apply it to fish keratocytes, fast moving cells that maintain their morphology, and show that we are able to reproduce recent experimental results on actin flow and stress patterns. Furthermore, we explore the phase diagram of cell motility by varying myosin II activity and adhesion strength. Our model suggests that the pattern of the actin flow inside the cell, the cell velocity, and the cell morphology are determined by the integration of actin polymerization, myosin contraction, adhesion forces, and membrane forces.

SUBMITTER: Shao D

PROVIDER: S-EPMC3344950 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Publications

Coupling actin flow, adhesion, and morphology in a computational cell motility model.

Shao Danying D Levine Herbert H Rappel Wouter-Jan WJ

Proceedings of the National Academy of Sciences of the United States of America 20120409 18

Cell migration is a pervasive process in many biology systems and involves protrusive forces generated by actin polymerization, myosin dependent contractile forces, and force transmission between the cell and the substrate through adhesion sites. Here we develop a computational model for cell motion that uses the phase-field method to solve for the moving boundary with physical membrane properties. It includes a reaction-diffusion model for the actin-myosin machinery and discrete adhesion sites ...[more]

PMID: 22493219

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Project description:Lymphocytes have been described to perform different motility patterns such as Brownian random walks, persistent random walks, and Lévy walks. Depending on the conditions, such as confinement or the distribution of target cells, either Brownian or Lévy walks lead to more efficient interaction with the targets. The diversity of these motility patterns may be explained by an adaptive response to the surrounding extracellular matrix (ECM). Indeed, depending on the ECM composition, lymphocytes either display a floating motility without attaching to the ECM, or sliding and stepping motility with respectively continuous or discontinuous attachment to the ECM, or pivoting behaviour with sustained attachment to the ECM. Moreover, on the long term, lymphocytes either perform a persistent random walk or a Brownian-like movement depending on the ECM composition. How the ECM affects cell motility is still incompletely understood. Here, we integrate essential mechanistic details of the lymphocyte-matrix adhesions and lymphocyte intrinsic cytoskeletal induced cell propulsion into a Cellular Potts model (CPM). We show that the combination of de novo cell-matrix adhesion formation, adhesion growth and shrinkage, adhesion rupture, and feedback of adhesions onto cell propulsion recapitulates multiple lymphocyte behaviours, for different lymphocyte subsets and various substrates. With an increasing attachment area and increased adhesion strength, the cells' speed and persistence decreases. Additionally, the model predicts random walks with short-term persistent but long-term subdiffusive properties resulting in a pivoting type of motility. For small adhesion areas, the spatial distribution of adhesions emerges as a key factor influencing cell motility. Small adhesions at the front allow for more persistent motility than larger clusters at the back, despite a similar total adhesion area. In conclusion, we present an integrated framework to simulate the effects of ECM proteins on cell-matrix adhesion dynamics. The model reveals a sufficient set of principles explaining the plasticity of lymphocyte motility.

Project description:Protrusion and retraction of lamellipodia are common features of eukaryotic cell motility. As a cell migrates through its extracellular matrix (ECM), lamellipod growth increases cell-ECM contact area and enhances engagement of integrin receptors, locally amplifying ECM input to internal signaling cascades. In contrast, contraction of lamellipodia results in reduced integrin engagement that dampens the level of ECM-induced signaling. These changes in cell shape are both influenced by, and feed back onto ECM signaling. Motivated by experimental observations on melanoma cells lines (1205Lu and SBcl2) migrating on fibronectin (FN) coated topographic substrates (anisotropic post-density arrays), we probe this interplay between intracellular and ECM signaling. Experimentally, cells exhibited one of three lamellipodial dynamics: persistently polarized, random, or oscillatory, with competing lamellipodia oscillating out of phase (Park et al., 2017). Pharmacological treatments, changes in FN density, and substrate topography all affected the fraction of cells exhibiting these behaviours. We use these observations as constraints to test a sequence of hypotheses for how intracellular (GTPase) and ECM signaling jointly regulate lamellipodial dynamics. The models encoding these hypotheses are predicated on mutually antagonistic Rac-Rho signaling, Rac-mediated protrusion (via activation of Arp2/3 actin nucleation) and Rho-mediated contraction (via ROCK phosphorylation of myosin light chain), which are coupled to ECM signaling that is modulated by protrusion/contraction. By testing each model against experimental observations, we identify how the signaling layers interact to generate the diverse range of cell behaviors, and how various molecular perturbations and changes in ECM signaling modulate the fraction of cells exhibiting each. We identify several factors that play distinct but critical roles in generating the observed dynamic: (1) competition between lamellipodia for shared pools of Rac and Rho, (2) activation of RhoA by ECM signaling, and (3) feedback from lamellipodial growth or contraction to cell-ECM contact area and therefore to the ECM signaling level.

Dataset Information

Coupling actin flow, adhesion, and morphology in a computational cell motility model.

Publications

Coupling actin flow, adhesion, and morphology in a computational cell motility model.

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