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Register a new userDensity fluctuations and border forces direct leader cell plasticity during collective epithelial migrations
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Epithelial cell monolayers expand on substrates by forming finger-like protrusions, created by leader cells, in the monolayer boundary. Information transmission and communication between individual entities in the cohesive collective lead to long-range order, vortical structures, and disorder to ordered phase transitions. We ask the following questions: what makes a leader? What is the role of followers in leader cell formation? We used a particle-based model to simulate epithelial cell migrations on substrates of 9.4 kPa, 21 kPa and 33 kPa stiffness. The dynamics of cellular motion in the ensemble are governed by orientational Vicsek and inter-cellular interactions between neighboring particles. The model also includes bending, curvature-based motility, and acto-myosin contractile cable forces on the contour, in addition to density dependent noise and cell proliferations. We show that border forces are essential in the leader cell formation and the overall areal expansions of epithelial monolayers on substrates. Radial velocities and areal expansions of the monolayer agree with experiments reported for epithelial cells on substrates of varied stiffness. Ordering in follower cells within a specific region of the monolayer was apparent on substrates of higher stiffness and occurred prior to the emergence of leader cells. We demonstrate that regions of increased cell density occur behind the leader cell edge on all three substrates. Finally, we assessed the role of cell divisions on the ordering of velocities in the monolayer. These results demonstrate that monolayer heterogeneities, caused by density instabilities in the interior regions, correlate with leader cell formation during epithelial migrations.
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Collective cell migration is crucial in many biological processes such as wound healing, tissue morphogenesis, and tumor progression. The leading front of a collective migrating epithelial cell layer often destabilizes into multicellular finger-like protrusions, each of which is guided by a leader cell at the fingertip. Here, we develop a subcellular-element-based model of this fingering instability, which incorporates leader cells and other related properties of a monolayer of epithelial cells. Our model recovers multiple aspects of the dynamics, especially the traction force patterns and velocity fields, observed in experiments on MDCK cells. Our model predicts the necessity of the leader cell and its minimal functions for the formation and maintenance of a stable finger pattern. Meanwhile, our model allows for an analysis of the role of supra-cellular actin cable on the leading front, predicting that while this observed structure helps maintain the shape of the finger, it is not required in order to form a finger. In addition, we also study the driving instability in the context of continuum active fluid model, which justifies some of our assumptions in the computational approach. In particular, we show that in our model no finger protrusions would emerge in a phenotypically homogenous active fluid and hence the role of the leader cell and its followers are often critical.
We introduce an Active Vertex Model (AVM) for cell-resolution studies of the mechanics of confluent epithelial tissues consisting of tens of thousands of cells, with a level of detail inaccessible to similar methods. The AVM combines the Vertex Model for confluent epithelial tissues with active matter dynamics. This introduces a natural description of the cell motion and accounts for motion patterns observed on multiple scales. Furthermore, cell contacts are generated dynamically from positions of cell centres. This not only enables efficient numerical implementation, but provides a natural description of the T1 transition events responsible for local tissue rearrangements. The AVM also includes cell alignment, cell-specific mechanical properties, cell growth, division and apoptosis. In addition, the AVM introduces a flexible, dynamically changing boundary of the epithelial sheet allowing for studies of phenomena such as the fingering instability or wound healing. We illustrate these capabilities with a number of case studies.
Key to collective cell migration is the ability of cells to rearrange their position with respect to their neighbors. Recent theory and experiments demonstrated that cellular rearrangements are facilitated by cell shape, with cells having more elongated shapes and greater perimeters more easily sliding past their neighbors within the cell layer. Though it is thought that cell perimeter is controlled primarily by cortical tension and adhesion at each cells periphery, experimental testing of this hypothesis has produced conflicting results. Here we studied collective cell migration in an epithelial monolayer by measuring forces, cell perimeters, and motion, and found all three to decrease with either increased cell density or inhibition of cell contraction. In contrast to previous understanding, the data suggest that cell shape and rearrangements are controlled not by cortical tension or adhesion at the cell periphery but rather by the stress fibers that produce tractions at the cell-substrate interface. This finding is confirmed by an experiment showing that increasing tractions reverses the effect of density on cell shape and rearrangements. Our study therefore reduces the focus on the cell periphery by establishing cell-substrate traction as a major physical factor controlling cell shape and motion in collective cell migration.
Cells coexist together in colonies or as tissues. Their behaviour is controlled by an interplay between intercellular forces and biochemical regulation. We develop a simple model of the cell cycle, the fundamental regulatory network controlling growth and division, and couple this to the physical forces arising within the cell collective. We analyse this model using both particle-based computer simulations and a continuum theory. We focus on 2D colonies confined in a channel. These develop moving growth fronts of dividing cells with quiescent cells in the interior. The profile and speed of these fronts are non-trivially related to the substrate friction and the cell cycle parameters, providing a possible approach to measure such parameters in experiments.
Epithelial cell clusters often move collectively on a substrate. Mechanical signals play a major role in organizing this behavior. There are a number of experimental observations in these systems which await a comprehensive explanation. These include: the internal strains are tensile even for clusters that expand by proliferation; the tractions on the substrate are often confined to the edges of the cluster; there can exist density waves within the cluster; clusters can exhibit collective durotaxis when individual cells show no effect; and for cells in an annulus there is a transition between expanding clusters with proliferation and the case where cells fill the annulus and rotate around it. We formulate a mechanical model to examine these effects. We use a molecular clutch picture which allows stalling -- inhibition of cell contraction by external forces. Stalled cells are passive from a physical point of view and the un-stalled cells are active. By attaching cells to the substrate and to each other, and taking into account contact inhibition of locomotion, we get a simple picture for many of these findings as well as predictions that could be tested. SI text/figures included, SI movies at https://rice.box.com/s/xiy3mwsfj3203lfu7pk0udfklexcgsew
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