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, 112 (11), 2419-2427

Cell Division Induces and Switches Coherent Angular Motion Within Bounded Cellular Collectives

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Cell Division Induces and Switches Coherent Angular Motion Within Bounded Cellular Collectives

Michael J Siedlik et al. Biophys J.

Abstract

Collective cell migration underlies many biological processes, including embryonic development, wound healing, and cancer progression. In the embryo, cells have been observed to move collectively in vortices using a mode of collective migration known as coherent angular motion (CAM). To determine how CAM arises within a population and changes over time, here, we study the motion of mammary epithelial cells within engineered monolayers, in which the cells move collectively about a central axis in the tissue. Using quantitative image analysis, we find that CAM is significantly reduced when mitosis is suppressed. Particle-based simulations recreate the observed trends, suggesting that cell divisions drive the robust emergence of CAM and facilitate switches in the direction of collective rotation. Our simulations predict that the location of a dividing cell, rather than the orientation of the division axis, facilitates the onset of this motion. These predictions agree with experimental observations, thereby providing, to our knowledge, new insight into how cell divisions influence CAM within a tissue. Overall, these findings highlight the dynamic nature of CAM and suggest that regulating cell division is crucial for tuning emergent collective migratory behaviors, such as vortical motions observed in vivo.

Figures

Figure 1
Figure 1
2D microfabricated mammary epithelial tissues exhibit CAM. Epithelial monolayers of defined geometry were produced by (a) microcontact printing micrometer-scale islands of fibronectin onto a silicone surface and seeding phenotypically normal mammary epithelial cells onto these regions, resulting in (b) confluent epithelial tissues. Cells within these tissues exhibit CAM, as observed in (c) the displacement field and (d) image sequence of a representative tissue. Three cells in (d) are outlined to ease visualization of CAM. The scale bars represent (a) 50 μm and (bd) 10 μm. To see this figure in color, go online.
Figure 2
Figure 2
The direction of rotation switches over time. (a) Three different periods of CAM (orange, green, and yellow) during the observation of a given tissue demonstrate that the direction of CAM can switch over a 24-h period of observation. A subset of nuclei are highlighted to help visualize rotational motion. The scale bars represent 10 μm. (b) The best-fit bulk rotational motion of a tissue, θ(t), is determined by comparing the measured positions of the cells with those predicted if the tissue were subjected to purely rotational or translational motion. See Materials and Methods. (c) Periods of CAM can be observed within a representative tissue as periods of steadily increasing or decreasing θ(t). This representative tissue shows switches in the direction of CAM over the duration of observation. Note that the colored regions correspond to the periods of CAM illustrated in (a). Red bars indicate a cell division event. (d) The rotational velocities of tissues often switch sign, indicating a change in direction, as the tissue density increases because of cell division. The solid lines connect periods of CAM that are observed in a given tissue as time and density increase. To see this figure in color, go online.
Figure 3
Figure 3
Blocking cell division impairs CAM within tissues. (a) Treatment with mitomycin C abolishes cell divisions over a 14 hr period of observation. (b) Untreated tissues exhibit greater CAM compared to (c) tissues treated with mitomycin C. (d) The fraction of tissues exhibiting at least one period of CAM is significantly reduced in tissues treated with mitomycin C, as compared to untreated tissues. (e) The fraction of rotating tissues that exhibit switches in the direction of CAM is significantly reduced in tissues treated with mitomycin C, as compared to untreated tissues. To generate these plots, rotational motion starting 90 minutes after the beginning of experimental observation was analyzed to ensure that cell division did not immediately precede the period of analysis. p < 0.05. To see this figure in color, go online.
Figure 4
Figure 4
Simulated tissues exhibit dynamic CAM and recreate the experimentally observed trends. (a) Two different periods of CAM observed in a simulated tissue. These simulations occurred within a square region corresponding to the experimental tissue boundaries. See Materials and Methods. Note that the indicated simulation times correspond to analogous experimental times. (b) Dynamic CAM is observed in simulated tissues that include cell division. The colored regions correspond to the periods of CAM illustrated in (a). Red bars indicate a cell division event. (c) Simulated tissues that do not include cell divisions do not exhibit dynamic CAM. (d and e) The model reproduces division-dependent trends that are observed experimentally, namely (d) the fraction of tissues undergoing CAM and (e) the fraction of rotating tissues that switch direction. The experimental data correspond to those depicted in Fig. 3, d and e. To see this figure in color, go online.
Figure 5
Figure 5
Simulations and experiments suggest that the location of cell division influences the onset of CAM. (a) To evaluate whether the position of a dividing cell within the tissue might contribute to the onset of CAM, all divisions were binned by radial position. In both (b) simulations and (c) experiments, divisions at the periphery of the tissue more frequently precede a period of CAM than divisions closer to the tissue center. (d) Similarly, cell divisions were binned by the angle along which the cell divides to determine whether this property might contribute to CAM. In this case, (e) simulations and (f) experiments both reveal that the orientation of the division axis does not preferentially promote CAM. p < 0.05. To see this figure in color, go online.

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