Dimensions in cell migration
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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2022, Biophysical JournalCitation Excerpt :While 2D migration allows for the investigation of the navigation abilities of cells, 1D migration through microchannels enforces confinement all around the sides of the cell, which might be more reflective of the local geometries that they encounter during in vivo migration through very tight spaces. It should be noted that the required degree of lateral confinement to have a 1D or 2D ameboid migration differs from that of an adherent mesenchymal migration (68,69) as the migration mechanisms are different: while the cells use integrins to adhere, transmit forces, and move in the mesenchymal migration, nonspecific friction forces are used in the ameboid migration mode (23,70). The cross section size of the microchannel in our 1D setup or the spacing between the parallel plates in the 2D setup should be small enough that the BDMCs can form the required frictional contacts with walls; otherwise the cells remain immobile.