Dimensions in cell migration

doi:10.1016/j.ceb.2013.06.004

Current Opinion in Cell Biology

Volume 25, Issue 5, October 2013, Pages 642-649

https://doi.org/10.1016/j.ceb.2013.06.004 Get rights and content

The importance of cell migration for both normal physiological functions and disease processes has been clear for the past 50 years. Although investigations of two-dimensional (2D) migration in regular tissue culture have elucidated many important molecular mechanisms, recent evidence suggests that cell migration depends profoundly on the dimensionality of the extracellular matrix (ECM). Here we review a number of evolving concepts revealed when cell migration is examined in different dimensions.

Introduction

Cell migration is crucial for numerous physiological and developmental processes, including gastrulation, organ formation, immune function, and wound healing. In addition, aberrant cell motility contributes to diseases such as cancer metastasis [1•, 2]. Initial characterizations of fibroblast motility in tissue culture helped to establish key concepts about cell migration based on adhesion and interactions with a 2D planar surface. These observations continue to guide current research on the intracellular regulation of signaling pathways involved in migration. However, the physical characteristics of an ECM can also strongly modulate cell migration by outside-in signaling from the microenvironment. Over the past decade, modeling of cell motility in three-dimensional (3D) ECM models that mimic more-physiological in vivo conditions has revealed substantial differences between 2D and 3D cellular migration. Besides these 3D models, simplified reductionist model systems have allowed analysis of matrix regulation of migration under more controllable experimental conditions [3, 4, 5, 6, 7]. In this review, we will explore recent conceptual advances in cell migration from investigations of cell migration in different dimensions using a variety of model systems. We will focus on how the unique dimensional aspects of 2D planar substrates, 3D scaffolds, and simplified one-dimensional (1D) fibers can help regulate migration rate, the mode of migration, cellular mechanotransduction, and cell signaling of mesenchymal-derived fibroblasts, but allude to other cell types when appropriate.

Section snippets

Overview of dimensional concepts in cell migration

As illustrated in Figure 1 (right panel), multiple intracellular regulatory mechanisms are known to govern adhesion-dependent fibroblast migration. Compounding this internal regulation, it is now clear that a host of ECM microenvironmental properties can directly influence these intracellular regulatory mechanisms to control the mode and rates of cell migration (Figure 1, left panels). The three primary classes of dimensionality involve 2D planar substrates classically used in cell culture, 1D

Control of cell migration through ECM topography

When comparing migration in different dimensions, a key ECM-dependent regulator involves differences in ECM topography. In a classic 2D migration model, ECM molecules are presented to cells as a flat sheet of globular molecules without appreciable fibrillar structure. This planar ECM topography promotes a spread cell morphology, and fibroblasts acquire a “hand-mirror” appearance (Figure 2a) with apical/basal polarity in cell adhesions and most of the contractile apparatus associated with the 2D

Dimensional control of cell migration through ECM–ligand interactions

Interactions between integrins and the ECM can profoundly affect migration rate and cell phenotype. 2D fibroblast migration rates demonstrate a biphasic dependence on ECM ligand density: cells on too little ECM fail to generate adhesions to the underlying substrate, whereas too much ECM inhibits cell tail retraction, reducing leading edge protrusion and slowing migration rate [19]. Optimal 2D migration rate occurs at intermediate levels, but the optimum can be shifted toward higher or lower ECM

Regulation of cell migration by ECM rheological readout

The rheological or elastic properties of an ECM can be “sensed” by a cell and can directly regulate intracellular functions. At the heart of this physical sensing mechanism is the mechanical link between the ECM and the actin-myosin contractile apparatus through cell adhesion sites [25, 26, 27]. Cells demonstrate a relatively proportional contractile response to the rigidity of the local microenvironment: adhesion size and number of stress fibers increase with ECM rigidity [28, 29]. Because of

The dependence of migration mode on ECM elastic behavior

Cells migrating on 2D surfaces predominantly use lamellipodia-based motility, in which actin polymerization against the plasma membrane over a broad area pushes the leading edge forward, followed by adhesion to the underlying substrate via integrin-dependent adhesions [36, 37, 38]. However, lamellipodia (Figure 2d) are only one of several types of protrusive elements generated by motile cells (recently reviewed in [39]), and in 3D environments the elastic behavior of the ECM in part governs the

Dimensionality and signaling in cell migration

Traditional 2D cell migration models have facilitated the identification of cell-matrix receptors, cytoskeletal machinery, and other intracellular regulators required for migration. However, the relative importance and roles of many of these molecules differ in recent analyses comparing migration in 3D ECM. As discussed earlier, cells in 3D and 1D fibrillar matrix models require actomyosin contractility for efficient migration; inhibition of myosin II activity decreases migration rates in 1D

Conclusions

Our review has touched upon selected recent investigations that illustrate important differences associated with cell migration in different dimensions, as well as the high context-dependence of migration due to specific ECM regulators of migration in each dimension. ECM composition, ECM stiffness, topography, elastic behavior, and other key biochemical and physical properties of the microenvironment initiate cellular adaptations that alter the overall mode of cell migration and the signaling

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We thank Emily Joo and Duy Tran for critically reviewing this manuscript and Tim Lammermann for helpful suggestions. Support was provided by the intramural research program of the National Institute of Dental and Craniofacial Research at the National Institutes of Health.

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Migrating cells traverse a range of topographic configurations presented by the native extracellular environment to conduct their physiologic functions. It is well documented cells can modulate their behaviour in response to different topographic features, finding promising applications in biomaterial and bioimplant design. It is useful, in these areas of research, to be able to predict which topographic arrangements could be used to promote certain patterns of migration prior to laboratory experimentation. Despite a profusion of study and interest shown in these fields by experimentalists, the related modelling literature is as yet relatively sparse and tend to focus more on either cell–matrix interaction or morphological responses of cells. We propose a mathematical model for individual cell migration based on an Ornstein–Uhlenbeck process, and set out to see if the model can be used to predict migration patterns on 2-d isotropic and anisotropic topographies, whose characteristics can be broadly described as either uniform flat, uniform linear with variable ridge density or non-uniform disordered with variable feature density. Results suggest the model is capable of producing realistic patterns of migration for flat and linear topographic patterns, with calibrated output closely approximating NIH3T3 fibroblast migration behaviour derived from an experimental dataset, in which migration linearity increased with ridge density and average speed was highest at intermediate ridge densities. Exploratory results for non-uniform disordered topographies suggest cell migration patterns may adopt disorderedness present in the topography and that ‘distortion’ introduced to linear topographic patterns may not impede linear guidance of migration, given its magnitude is bounded within certain limits. We conclude that an Ornstein–Uhlenbeck based model for topographically influenced migration may be useful to predict patterns of migration behaviour for certain isotropic (flat) and anisotropic (linear) topographies in the NIH3T3 fibroblast cell line, but additional investigation is required to predict with confidence migration patterns for non-uniform disordered topographic arrangements.
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Citation Excerpt :
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Published by Elsevier Ltd.

Dimensions in cell migration

Introduction

Section snippets

Overview of dimensional concepts in cell migration

Control of cell migration through ECM topography

Dimensional control of cell migration through ECM–ligand interactions

Regulation of cell migration by ECM rheological readout

The dependence of migration mode on ECM elastic behavior

Dimensionality and signaling in cell migration

Conclusions

References and recommended reading

Acknowledgements

J Cell Sci

Nat Methods

Am J Pathol

Science

Exp Neurol

Nature

Cell

J Cell Sci

J Cell Physiol

Ann Biomed Eng

Cell

J Cell Biol

Trends Cell Biol

J Cell Biol

Mol Biol Cell

J Cell Sci

Integr Biol (Camb)

Cell Adh Migr

J Biol Chem

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium

Proc Natl Acad Sci U S A

Cell migration: integrating signals from front to back

Science

Guidance of cell migration by substrate dimension

Biophys J

One-dimensional topography underlies three-dimensional fibrillar cell migration

J Cell Biol

Two-photon laser-generated microtracks in 3D collagen lattices: principles of MMP-dependent and -independent collective cancer cell invasion

Phys Biol

Microfabricated collagen tracks facilitate single cell metastatic invasion in 3D

Integr Biol (Camb)

Elucidating the role of matrix stiffness in 3D cell migration and remodeling

Biophys J

Pushing off the walls: a mechanism of cell motility in confinement

Phys Rev Lett

Plasticity of cell migration: a multiscale tuning model

J Cell Biol

Direct comparisons of the morphology, migration, cell adhesions, and actin cytoskeleton of fibroblasts in four different three-dimensional extracellular matrices

Tissue Eng A

Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization

Biophys J

Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis

Cell