The role of actin protrusion dynamics in cell migration through a degradable viscoelastic extracellular matrix: Insights from a computational model

AbstractActin protrusion dynamics plays an important role in the regulation of three-dimensional (3D) cell migration. Cells form protrusions that adhere to the surrounding extracellular matrix (ECM), mechanically probe the ECM and contract in order to displace the cell body. This results in cell migration that can be directed by the mechanical anisotropy of the ECM. However, the subcellular processes that regulate protrusion dynamics in 3D cell migration are difficult to investigate experimentally and therefore not well understood. Here, we present a computational model of cell migration through a degradable viscoelastic ECM. The cell is modeled as an active deformable object that captures the viscoelastic behavior of the actin cortex and the subcellular processes underlying 3D cell migration. The ECM is regarded as a viscoelastic material, with or without anisotropy due to fibrillar strain stiffening, and modeled by means of the meshless Lagrangian smoothed particle hydrodynamics (SPH) method. ECM degradation is captured by local fluidization of the material and permits cell migration through the ECM. We demonstrate that changes in ECM stiffness and cell strength affect cell migration and are accompanied by changes in number, lifetime and length of protrusions. Interestingly, directly changing the total protrusion number or the average lifetime or length of protrusions does not affect cell migration. A stochastic variability in protrusion lifetime proves to be enough to explain differences in cell migration velocity. Force-dependent adhesion disassembly does not result in faster migration, but can make migration more efficient. We also demonstrate that when a number of simultaneous protrusions is enforced, the optimal number of simultaneous protrusions is one or two, depending on ECM anisotropy. Together, the model provides non-trivial new insights in the role of protrusions in 3D cell migration and can be a valuable contribution to increase the understanding of 3D cell migration mechanics.Author summaryThe ability of cells to migrate through a tissue in the human body is vital for many processes such as tissue development, growth and regeneration. At the same time, abnormal cell migration is also playing an important role in many diseases such as cancer. If we want to be able to explain the origin of these abnormalities and develop new treatment strategies, we have to understand how cells are able to regulate their migration. Since it is challenging to investigate cell migration through a biological tissue in experiments, computational modeling can provide a valuable contribution. We have developed a computational model of cell migration through a deformable and degradable material that describes both mechanics of the cell and the surrounding material and subcellular processes underlying cell migration. This model captures the formation of long and thin protrusions that adhere to the surrounding material and that pull the cell forward. It provides new non-trivial insights in the role of these protrusions in cell migration and the regulation of protrusion dynamics by cell strength and anisotropic mechanical properties of the surrounding material. Therefore, we believe that this model can be a valuable tool to further improve the understanding of cell migration.

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The role of actin protrusion dynamics in cell migration through a degradable viscoelastic extracellular matrix: Insights from a computational model

PLoS Computational Biology ◽

10.1371/journal.pcbi.1007250 ◽

2020 ◽

Vol 16 (1) ◽

pp. e1007250 ◽

Cited By ~ 14

Author(s):

Tommy Heck ◽

Diego A. Vargas ◽

Bart Smeets ◽

Herman Ramon ◽

Paul Van Liedekerke ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Migration ◽

Computational Model

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A Histopathologic Analysis of Atherectomized Human Coronary Stent Restenosis :Potential Role of Cell Migration and Extracellular Matrix Formation

Korean Circulation Journal ◽

10.4070/kcj.1999.29.2.228 ◽

1999 ◽

Vol 29 (2) ◽

pp. 228

Author(s):

Ick-Mo Chung ◽

Woo Ick Yang

Keyword(s):

Extracellular Matrix ◽

Cell Migration ◽

Potential Role ◽

Coronary Stent ◽

Stent Restenosis ◽

Histopathologic Analysis

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Insights into the local pathogenesis induced by fish toxins: Role of natterins and nattectin in the disruption of cell–cell and cell–extracellular matrix interactions and modulation of cell migration

Toxicon ◽

10.1016/j.toxicon.2011.08.012 ◽

2011 ◽

Vol 58 (6-7) ◽

pp. 509-517 ◽

Cited By ~ 12

Author(s):

Evilin Naname Komegae ◽

Anderson Daniel Ramos ◽

Ana Karina Oliveira ◽

Solange Maria de Toledo Serrano ◽

Mônica Lopes-Ferreira ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Migration ◽

Matrix Interactions ◽

Extracellular Matrix Interactions ◽

Cell Cell

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The role of amiloride sensitive epithelial sodium channel (ENaC) in cell migration of mesothelioma cells is dependent on the cell type and the extracellular matrix

10.1183/13993003.congress-2016.pa5072 ◽

2016 ◽

Author(s):

Rajesh Jagirdar ◽

Paschalis Adam Molyvdas ◽

Konstantinos Gourgoulianis ◽

Chrissi Hatzoglou ◽

Sotirios Zarogiannis

Keyword(s):

Extracellular Matrix ◽

Cell Migration ◽

Sodium Channel ◽

Epithelial Sodium Channel ◽

Cell Type ◽

Epithelial Sodium Channel Enac

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Role of high molecular weight extracellular matrix proteins in glioma cell migration

Neuropathology and Applied Neurobiology ◽

10.1111/j.1365-2990.1997.tb01192.x ◽

1997 ◽

Vol 23 (2) ◽

pp. 102-112 ◽

Cited By ~ 20

Author(s):

R. Mahesparan ◽

B. B. Tysnes ◽

K. Edvardsen ◽

H. K. Haugeland ◽

I. Garcia Cabrera ◽

...

Keyword(s):

Molecular Weight ◽

Extracellular Matrix ◽

Cell Migration ◽

High Molecular Weight ◽

Glioma Cell ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Glioma Cell Migration

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One-dimensional topography underlies three-dimensional fibrillar cell migration

The Journal of Cell Biology ◽

10.1083/jcb.200810041 ◽

2009 ◽

Vol 184 (4) ◽

pp. 481-490 ◽

Cited By ~ 515

Author(s):

Andrew D. Doyle ◽

Francis W. Wang ◽

Kazue Matsumoto ◽

Kenneth M. Yamada

Keyword(s):

Cell Culture ◽

Extracellular Matrix ◽

Cell Migration ◽

Myosin Ii ◽

Three Dimensional ◽

Two Dimensional ◽

Ligand Density ◽

One Dimensional ◽

3D Cell Migration ◽

Striking Contrast

Current concepts of cell migration were established in regular two-dimensional (2D) cell culture, but the roles of topography are poorly understood for cells migrating in an oriented 3D fibrillar extracellular matrix (ECM). We use a novel micropatterning technique termed microphotopatterning (μPP) to identify functions for 1D fibrillar patterns in 3D cell migration. In striking contrast to 2D, cell migration in both 1D and 3D is rapid, uniaxial, independent of ECM ligand density, and dependent on myosin II contractility and microtubules (MTs). 1D and 3D migration are also characterized by an anterior MT bundle with a posterior centrosome. We propose that cells migrate rapidly through 3D fibrillar matrices by a 1D migratory mechanism not mimicked by 2D matrices.

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Computational estimates of mechanical constraints on cell migration through the extracellular matrix

10.1101/2020.01.19.912006 ◽

2020 ◽

Author(s):

Ondrej Maxian ◽

Alex Mogilner ◽

Wanda Strychalski

Keyword(s):

Extracellular Matrix ◽

Cell Migration ◽

Pressure Gradient ◽

Cell Body ◽

Fluid Pressure ◽

Three Dimensional ◽

Extracellular Fluid ◽

Cell Cortex ◽

3D Cell Migration ◽

Parameter Values

AbstractCell migration through a three-dimensional (3D) extracellular matrix (ECM) underlies important physiological phenomena and is based on a variety of mechanical strategies depending on the cell type and the properties of the ECM. By using computer simulations, we investigate two such migration mechanisms – ‘push-pull’ (forming a finger-like protrusion, adhering to an ECM node, and pulling the cell body forward) and ‘rear-squeezing’ (pushing the cell body through the ECM by contracting the cell cortex and ECM at the cell rear). We present a computational model that accounts for both elastic deformation and forces of the ECM, an active cell cortex and nucleus, and for hydrodynamic forces and flow of the extracellular fluid, cytoplasm and nucleoplasm. We find that relations between three mechanical parameters – the cortex’s contractile force, nuclear elasticity and ECM rigidity – determine the effectiveness of cell migration through the dense ECM. The cell can migrate persistently even if its cortical contraction cannot deform a near-rigid ECM, but then the contraction of the cortex has to be able to sufficiently deform the nucleus. The cell can also migrate even if it fails to deform a stiff nucleus, but then it has to be able to sufficiently deform the ECM. Simulation results show that nuclear stiffness limits the cell migration more than the ECM rigidity. Simulations of the rear-squeezing mechanism of motility results in more robust migration with larger cell displacements than those with the push-pull mechanism over a range of parameter values.Author summaryComputational simulations of models representing two different mechanisms of 3D cell migration in an extracellular matrix are presented. One mechanism represents a mesenchymal mode, characterized by finger-like actin protrusions, while the second mode is more amoeboid in that rear contraction of the cortex propels the cell forward. In both mechanisms, the cell generates a thin actin protrusion on the cortex that attaches to an ECM node. The cell is then either pulled (mesenchymal) or pushed (amoeboid) forward. Results show both mechanisms result in successful migration over a range of simulated parameter values as long as the contractile tension of the cortex exceeds either the nuclear stiffness or ECM stiffness, but not necessarily both. However, the distance traveled by the amoeboid migration mode is more robust to changes in parameter values, and is larger than in simulations of the mesenchymal mode. Additionally cells experience a favorable fluid pressure gradient when migrating in the amoeboid mode, and an adverse fluid pressure gradient in the mesenchymal mode.

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A Computational Model of Bio-Inspired Soft Network Materials for Analyzing Their Anisotropic Mechanical Properties

Journal of Applied Mechanics ◽

10.1115/1.4039815 ◽

2018 ◽

Vol 85 (7) ◽

Cited By ~ 8

Author(s):

Enrui Zhang ◽

Yuan Liu ◽

Yihui Zhang

Keyword(s):

Computational Model ◽

Rotational Symmetry ◽

Strain Curve ◽

Mechanical Anisotropy ◽

Stress Strain ◽

Good Correspondence ◽

Mechanical Responses ◽

Synthetic Materials ◽

Nonlinear Stress ◽

Anisotropic Mechanical Properties

Soft network materials constructed with horseshoe microstructures represent a class of bio-inspired synthetic materials that can be tailored precisely to match the nonlinear, J-shaped, stress–strain curves of human skins. Under a large level of stretching, the nonlinear deformations associated with the drastic changes of microstructure geometries can lead to an evident mechanical anisotropy, even for honeycomb and triangular lattices with a sixfold rotational symmetry. Such anisotropic mechanical responses are essential for certain targeted applications of these synthetic materials. By introducing appropriate periodic boundary conditions that apply to large deformations, this work presents an efficient computational model of soft network materials based on the analyses of representative unit cells. This model is validated through comparison of predicted deformed configurations with full-scale finite element analyses (FEA) for different loading angles and loading strains. Based on this model, the anisotropic mechanical responses, including the nonlinear stress–strain curves and Poisson's ratios, are systematically analyzed for three representative lattice topologies (square, triangular and honeycomb). An analytic solution of the geometry-based critical strain was found to show a good correspondence to the critical transition point of the calculated J-shaped stress–strain curve for different network geometries and loading angles. Furthermore, the nonlinear Poisson's ratio, which can be either negative or positive, was shown to depend highly on both the loading angle and the loading strain.

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