The crawling motility of many eukaryotic cells is driven by filamentous actin (F-actin), and regulated by a network of signaling proteins and lipids (including small GTPases). The tangle of positive and negative feedback loops gives rise to various experimentally observed dynamic patterns (actin waves). Here we consider a recent prototypical model for actin waves in which F-actin exerts negative feedback onto a GTPase. Guided by previous numerical PDE bifurcation analysis, we explore cell shapes and motility associated with polar, oscillatory, and traveling wave solutions of a mass-conserved partial differential equation (PDE) model. We use Morpheus (cellular Potts) simulations to investigate the implications of such regimes of behavior on the shapes and motion of cells, and on transitions between modes of behavior. The model demonstrates various cell states, including resting (spatially uniform GTPase activity), polar cells (static zones of GTPase activity), and traveling waves along the cell edge. In some parameter regimes, such states can coexist, so that cells can transition from one behavior to another in response to noisy stimuli.
The motility of a fish keratocyte on a flat substrate exhibits two distinct regimes: the non-migrating and the migrating one. In both configurations the shape is fixed in time and, when the cell is moving, the velocity is constant in magnitude and direction. Transition from a stable configuration to the other one can be produced by a mechanical or chemotactic perturbation. In order to point out the mechanical nature of such a bistable behaviour, we focus on the actin dynamics inside the cell using a minimal mathematical model. While the protein diffusion, recruitment and segregation govern the…
Crawling cell motility is vital to many biological processes such as wound healing and the immune response. Using a minimal model we investigate the effects of patterned substrate adhesiveness and biophysical cell parameters on the direction of cell motion. We show that cells with low adhesion site formation rates may move perpendicular to adhesive stripes while a those with high adhesion site formation rates results in motility only parallel to the substrate stripes. We explore the effects of varying the substrate pattern and the strength of actin polymerization on the directionality of the c…
We analyse a generic motility model, with the motility mechanism arising by contractile stress due to the interaction of myosin and actin. A hydrodynamic active polar gel theory is used to model the cytoplasm of a cell and is combined with a Helfrich-type model to account for membrane properties. The overall model allows to consider motility without the necessity for local adhesion. Besides a detailed numerical approach together with convergence studies for the highly nonlinear free boundary problem, we also compare the induced flow field of the motile cell with that of classical squirmer mode…
In the framework of a phase field model of a single cell crawling on a substrate, we investigate how the properties of the cell membrane affect the shape and motility of the cell. Since the membrane influences the cell dynamics on multiple levels and provides a nontrivial feedback, we consider the following fundamental interactions: (i) the reduction of the actin polymerization rate by membrane tension; (ii) area conservation of the cell's two-dimensional cross-section vs. conservation of its circumference (i.e. membrane inextensibility); and (iii) the contribution from the membrane's bending …
Substrate-based cell motility is essential for fundamental biological processes, such as tissue growth, wound healing and immune response. Even if a comprehensive understanding of this motility mode remains elusive, progress has been achieved in its modeling using a whole cell physical model. The model takes into account the main mechanisms of cell motility - actin polymerization, substrate mediated adhesion and actin-myosin dynamics and combines it with steric cell-cell and hydrodynamic interactions. The model predicts the onset of collective cell migration, which emerges spontaneously as a r…
The polarization and motility of eukaryotic cells depends on assembly and contraction of the actin cytoskeleton and its regulation by proteins called GTPases. The activity of GTPases causes assembly of filamentous actin (by GTPases Cdc42, Rac), resulting in protrusion of the cell edge. Mathematical models for GTPase dynamics address the spontaneous formation of patterns and nonuniform spatial distributions of such proteins in the cell. Here we revisit the wave-pinning model for GTPase-induced cell polarization, together with a number of extensions proposed in the literature. These include intr…
The selective insertion of foreign materials, such as fluorescent markers or plasmids, into living cells has been a challenging problem in cell biology.However, it is often necessary that researchers insert such materials into cells for various dynamical and/or drug delivery studies. This problem becomes even more challenging if the study is to be limited to specific cells within a larger population, since other transfection methods, such as viral transfection and lipofection, are not realizable with a high degree of spatial selectivity.Here, we have used a focused femtosecond laser beam to cr…
Amoeboid cell motility is relevant in a wide variety of biomedical applications such as wound healing, cancer metastasis, and embryonic morphogenesis. It is characterized by pronounced changes of the cell shape associated with expansions and retractions of the cell membrane, which result in a crawling kind of locomotion. Despite existing computational models of amoeboid motion, the inference of expansion and retraction components of individual cells, the corresponding classification of cells, and the a priori specification of the parameter regime to achieve a specific motility behavior remain …
The motility of adherent eukaryotic cells is driven by the dynamics of the actin cytoskeleton. Despite the common force-generating actin machinery, different cell types often show diverse modes of locomotion that differ in their shape dynamics, speed, and persistence of motion. Recently, experiments in Dictyostelium discoideum have revealed that different motility modes can be induced in this model organism, depending on genetic modifications, developmental conditions, and synthetic changes of intracellular signaling. Here, we report experimental evidence that in a mutated D. discoideum cell l…
Suspensions of swimming micro-organisms provide examples of coordinated active dynamics. That has stimulated the study of a phenomenological theory combining synchronization and polar order in active matter. Here, we consider another example inspired by the traction forces of migrating cells. The novelty, in this case, is the global force-free nature of the traction force field. Such a constraint is absent in the case where the vector field describes swimming speeds in micro-organisms suspensions. Cell traction is characterized by means of a complex tensor quantity, that generalizes the nemati…
Eukaryotic cells adhere to extracellular matrix during the normal development of the organism, forming static adhesion as well as during cell motility. We study this process by considering a simplified coarse-grained model of a vesicle that has uniform adhesion energy with a flat substrate, mobile curved membrane proteins and active forces. We find that a high concentration of curved proteins alone increases the spreading of the vesicle, by the self-organization of the curved proteins at the high curvature vesicle-substrate contact line, thereby reducing the bending energy penalty at the vesic…
During the last decade, intracellular actin waves have attracted much attention due to their essential role in various cellular functions, ranging from motility to cytokinesis. Experimental methods have advanced significantly and can capture the dynamics of actin waves over a large range of spatio-temporal scales. However, the corresponding coarse-grained theory mostly avoids the full complexity of this multi-scale phenomenon. In this perspective, we focus on a minimal continuum model of activator-inhibitor type and highlight the qualitative role of mass-conservation, which is typically overlo…
The migration behaviors of cancer cells are known to be heterogeneous. However, the interplay between the adhesion interactions, dynamical shape changes and fluid flows in regulating cell migration heterogeneity and plasticity during cancer metastasis is still elusive. To further quantitative understanding of cell motility and morphology, we develop a theory using stochastic quantization method that describes the role of biophysical cues in regulating diverse cell motility. We show that the cumulative effect of time dependent adhesion interactions that determine the structural rearrangements a…
Cell motility in higher organisms (eukaryotes) is crucial to biological functions ranging from wound healing to immune response, and also implicated in diseases such as cancer. For cells crawling on hard surfaces, significant insights into motility have been gained from experiments replicating such motion in vitro. Such experiments show that crawling uses a combination of actin treadmilling (polymerization), which pushes the front of a cell forward, and myosin-induced stress (contractility), which retracts the rear. Here we present a simplified physical model of a crawling cell, consisting of …
Bistability of travelling waves and wave-pinning states in a mass-conserved reaction-diffusion system: From bifurcations to implications for actin waves
University of British Columbia（不列颠哥伦比亚大学）；Ben-Gurion University of the Negev（内盖夫本-古里安大学）；Swiss Institute for Dryland Environmental and Energy Research, Blaustein Institutes for Desert Research（瑞士旱地环境与能源研究所，布拉斯泰因沙漠研究所）
We study a minimal model of a crawling eukaryotic cell with a chemical polarity controlled by a reaction-diffusion mechanism describing Rho GTPase dynamics. The size, shape, and speed of the cell emerge from the combination of the chemical polarity, which controls the locations where actin polymerization occurs, and the physical properties of the cell, including its membrane tension. We find in our model both highly persistent trajectories, in which the cell crawls in a straight line, and turning trajectories, where the cell transitions from crawling in a line to crawling in a circle. We discu…
Drosophila melanogaster hemocytes are highly motile cells that are crucial for successful embryogenesis and have important roles in the organism's immunological response. Hemocyte motion was measured using selective plane illumination microscopy. Every hemocyte cell in one half of an embryo was tracked during embryogenesis and analysed using a deep learning neural network. The anomalous transport of the cells was well described by fractional Brownian motion that was heterogeneous in both time and space. Hemocyte motion became less persistent over time. LanB1 and SCAR mutants disrupted the coll…
During migration cells exhibit a rich variety of seemingly random migration patterns, which makes unraveling the underlying mechanisms that control cell migration a daunting challenge. For efficient migration cells require a mechanism for polarization, so that traction forces are produced in the direction of motion, while adhesion is released to allow forward migration. To simplify the study of this process cells have been studied when placed along one-dimensional tracks, where single cells exhibit both smooth and stick-slip migration modes. The stick-slip motility mode is characterized by pro…
Cell polarization requires redistribution of specific proteins to the nascent front and back of a eukarytotic cell. Among these proteins are Rac and Rho, members of the small GTPase family that regulate the actin cytoskeleton. Rac promotes actin assembly and protrusion of the front edge, whereas Rho activates myosin-driven contraction at the back. Mathematical models of cell polarization at many levels of detail have appeared. One of the simplest based on "wave-pinning", consists of a pair of reaction-diffusion equations for a single GTPase. Mathematical analysis of wave-pinning so far is larg…
