A free-boundary model of a motile cell explains turning behavior

To understand shapes and movements of cells undergoing lamellipodial motility, we systematically explore minimal free-boundary models of actin-myosin contractility consisting of the force-balance and myosin transport equations. The models account for isotropic contraction proportional to myosin density, viscous stresses in the actin network, and constant-strength viscous-like adhesion. The contraction generates a spatially graded centripetal actin flow, which in turn reinforces the contraction via myosin redistribution and causes retraction of the lamellipodial boundary. Actin protrusion at the boundary counters the retraction, and the balance of the protrusion and retraction shapes the lamellipodium. The model analysis shows that initiation of motility critically depends on three dimensionless parameter combinations, which represent myosin-dependent contractility, a characteristic viscosity-adhesion length, and a rate of actin protrusion. When the contractility is sufficiently strong, cells break symmetry and move steadily along either straight or circular trajectories, and the motile behavior is sensitive to conditions at the cell boundary. Scanning of a model parameter space shows that the contractile mechanism of motility supports robust cell turning in conditions where short viscosity-adhesion lengths and fast protrusion cause an accumulation of myosin in a small region at the cell rear, destabilizing the axial symmetry of a moving cell.

[1]  Igor S. Aranson,et al.  Collisions of deformable cells lead to collective migration , 2015, Scientific Reports.

[2]  A. Carlsson,et al.  Mechanisms of cell propulsion by active stresses , 2011, New journal of physics.

[3]  Michael Sixt,et al.  Mechanical modes of 'amoeboid' cell migration. , 2009, Current opinion in cell biology.

[4]  Falko Ziebert,et al.  Model for self-polarization and motility of keratocyte fragments , 2012, Journal of The Royal Society Interface.

[5]  K. Doubrovinski,et al.  Self-organized cell motility from motor-filament interactions. , 2012, Biophysical journal.

[6]  Marc Herant,et al.  Form and function in cell motility: from fibroblasts to keratocytes. , 2010, Biophysical journal.

[7]  Eshel Ben-Jacob,et al.  Activated Membrane Patches Guide Chemotactic Cell Motility , 2011, PLoS Comput. Biol..

[8]  Leah Edelstein-Keshet,et al.  A Comparison of Computational Models for Eukaryotic Cell Shape and Motility , 2012, PLoS Comput. Biol..

[9]  G. Borisy,et al.  Cell Migration: Integrating Signals from Front to Back , 2003, Science.

[10]  Hans G. Othmer,et al.  A continuum model of motility in ameboid cells , 2004, Bulletin of mathematical biology.

[11]  Lingling Wu,et al.  A simple package for front tracking , 2006, J. Comput. Phys..

[12]  A. Mogilner,et al.  Model of polarization and bistability of cell fragments. , 2007, Biophysical journal.

[13]  F. Harlow,et al.  Cell motion, contractile networks, and the physics of interpenetrating reactive flow. , 1986, Biophysical journal.

[14]  A. Mogilner,et al.  Actin Disassembly 'clock' and Membrane Tension Determine Cell Shape and Turning: a Mathematical Model Actin Disassembly 'clock' and Membrane Tension Determine Cell Shape and Turning: a Mathematical Model , 2010 .

[15]  Elsen Tjhung,et al.  Spontaneous symmetry breaking in active droplets provides a generic route to motility , 2012, Proceedings of the National Academy of Sciences.

[16]  L. Segel,et al.  Model for chemotaxis. , 1971, Journal of theoretical biology.

[17]  Leah Edelstein-Keshet,et al.  A Computational Model of Cell Polarization and Motility Coupling Mechanics and Biochemistry , 2010, Multiscale Model. Simul..

[18]  Wouter-Jan Rappel,et al.  Coupling actin flow, adhesion, and morphology in a computational cell motility model , 2012, Proceedings of the National Academy of Sciences.

[19]  Gaudenz Danuser,et al.  Actin–myosin network reorganization breaks symmetry at the cell rear to spontaneously initiate polarized cell motility , 2007, The Journal of cell biology.

[20]  N G Cogan,et al.  Multiphase flow models of biogels from crawling cells to bacterial biofilms , 2010, HFSP journal.

[21]  Julie A. Theriot,et al.  Principles of locomotion for simple-shaped cells , 1993, Nature.

[22]  A. Verkhovsky The mechanisms of spatial and temporal patterning of cell-edge dynamics. , 2015, Current opinion in cell biology.

[23]  Kenneth M. Yamada,et al.  Multiple mechanisms of 3D migration: the origins of plasticity. , 2016, Current opinion in cell biology.

[24]  Dylan J.Altschuler,et al.  The Zoo of Solitons for Curve Shortening in $\R^n$ , 2012, 1207.4051.

[25]  F. Raynaud,et al.  Minimal model for spontaneous cell polarization and edge activity in oscillating, rotating and migrating cells , 2016, Nature Physics.

[26]  Wolfgang Alt,et al.  Continuum model of cell adhesion and migration , 2009, Journal of mathematical biology.

[27]  S. Grill,et al.  Pattern Formation in Active Fluids , 2011 .

[28]  R. Sibson,et al.  A brief description of natural neighbor interpolation , 1981 .

[29]  Nir S. Gov,et al.  Theoretical Model for Cellular Shapes Driven by Protrusive and Adhesive Forces , 2011, PLoS Comput. Biol..

[30]  J. Theriot,et al.  Crawling toward a unified model of cell mobility: spatial and temporal regulation of actin dynamics. , 2004, Annual review of biochemistry.

[31]  J. M. Oliver,et al.  Thin-film theories for two-phase reactive flow models of active cell motion. , 2005, Mathematical medicine and biology : a journal of the IMA.

[32]  Wouter-Jan Rappel,et al.  Crawling and turning in a minimal reaction-diffusion cell motility model: Coupling cell shape and biochemistry. , 2016, Physical review. E.

[33]  G. Somero,et al.  Influences of thermal acclimation and acute temperature change on the motility of epithelial wound-healing cells (keratocytes) of tropical, temperate and Antarctic fish , 2003, Journal of Experimental Biology.

[34]  Leslie M Loew,et al.  Use of virtual cell in studies of cellular dynamics. , 2010, International review of cell and molecular biology.

[35]  T. Svitkina,et al.  Network contraction model for cell translocation and retrograde flow. , 1999, Biochemical Society symposium.

[36]  Lee A. Segel,et al.  Averaged Equations for Two-Phase Flows , 1971 .

[37]  Joel H. Ferziger,et al.  Computational methods for fluid dynamics , 1996 .

[38]  Jelena Stajic,et al.  Redundant mechanisms for stable cell locomotion revealed by minimal models. , 2011, Biophysical journal.

[39]  Active self-polarization of contractile cells in asymmetrically shaped domains. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[40]  Roger Lui,et al.  Exploring the control circuit of cell migration by mathematical modeling. , 2008, Biophysical journal.

[41]  Alexandra Jilkine,et al.  Polarization and Movement of Keratocytes: A Multiscale Modelling Approach , 2006, Bulletin of mathematical biology.

[42]  Sean R. Collins,et al.  Locally excitable Cdc42 signals steer cells during chemotaxis , 2015, Nature Cell Biology.

[43]  A. Mogilner,et al.  Actin disassembly clock determines shape and speed of lamellipodial fragments , 2011, Proceedings of the National Academy of Sciences.

[44]  L S Kimpton,et al.  Multiple travelling-wave solutions in a minimal model for cell motility. , 2013, Mathematical medicine and biology : a journal of the IMA.

[45]  Masaki Sasai,et al.  Modulation of the reaction rate of regulating protein induces large morphological and motional change of amoebic cell. , 2006, Journal of theoretical biology.

[46]  Alex Mogilner,et al.  Multiscale Two-Dimensional Modeling of a Motile Simple-Shaped Cell , 2005, Multiscale Model. Simul..

[47]  Julie A. Theriot,et al.  An Adhesion-Dependent Switch between Mechanisms That Determine Motile Cell Shape , 2011, PLoS biology.

[48]  M. Shelley,et al.  Active contraction of microtubule networks , 2015, eLife.

[49]  The zoo of solitons for curve shortening in Rn Note , 2013 .

[50]  Eshel Ben-Jacob,et al.  Polarity mechanisms such as contact inhibition of locomotion regulate persistent rotational motion of mammalian cells on micropatterns , 2014, Proceedings of the National Academy of Sciences.

[51]  John A. Mackenzie,et al.  A computational method for the coupled solution of reaction–diffusion equations on evolving domains and manifolds: Application to a model of cell migration and chemotaxis , 2016, J. Comput. Phys..

[52]  D. Helbing,et al.  Molecular crowding creates traffic jams of kinesin motors on microtubules , 2012, Proceedings of the National Academy of Sciences.

[53]  Alex Mogilner,et al.  Comparison of cell migration mechanical strategies in three-dimensional matrices: a computational study , 2016, Interface Focus.

[54]  L. Truskinovsky,et al.  Contraction-driven cell motility. , 2013, Physical review letters.

[55]  M. Cates,et al.  A minimal physical model captures the shapes of crawling cells , 2015, Nature Communications.

[56]  Greg M. Allen,et al.  Article Electrophoresis of Cellular Membrane Components Creates the Directional Cue Guiding Keratocyte Galvanotaxis , 2022 .

[57]  Julie A. Theriot,et al.  Mechanism of shape determination in motile cells , 2008, Nature.

[58]  Igor L. Novak,et al.  A conservative algorithm for parabolic problems in domains with moving boundaries , 2014, J. Comput. Phys..

[59]  Erin L. Barnhart,et al.  Balance between cell−substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes , 2015, Proceedings of the National Academy of Sciences.

[60]  Wouter-Jan Rappel,et al.  Computational model for cell morphodynamics. , 2010, Physical review letters.

[61]  Erin L. Barnhart,et al.  Membrane Tension in Rapidly Moving Cells Is Determined by Cytoskeletal Forces , 2013, Current Biology.

[62]  Wanda Strychalski,et al.  Intracellular Pressure Dynamics in Blebbing Cells. , 2016, Biophysical journal.

[63]  Patrick W. Oakes,et al.  Disordered actomyosin networks are sufficient to produce cooperative and telescopic contractility , 2016, Nature Communications.

[64]  Ken Jacobson,et al.  Actin-myosin viscoelastic flow in the keratocyte lamellipod. , 2009, Biophysical journal.

[65]  Igor S. Aranson,et al.  Effects of Adhesion Dynamics and Substrate Compliance on the Shape and Motility of Crawling Cells , 2013, PloS one.