Abstract
Cells migrating in clusters play a significant role in a number of biological processes such as embryogenesis, wound healing, and tumor metastasis during cancer progression. A variety of environmental and biochemical factors can influence the collective migration of cells with differing degrees of cell autonomy and inter-cellular coupling strength. For example, weakly coupled cells can move collectively under the influence of contact guidance from neighboring cells or the environment. Alternatively strongly coupled cells might follow one or more leader cells to move as a single cohesive unit. Additionally, chemical and mechanical signaling between these cells may alter the degree of coupling and determine effective cluster sizes. Being able to understand this collective cell migration process is critical in the prediction and manipulation of outcomes of key biological processes. Here we focus on understanding how various environmental and cellular factors influence small clusters of cells migrating collectively within a 3D fibrous matrix. We combine existing knowledge of single-cell migration in 2D and 3D environments, prior experimental observations of cell–cell interactions and collective migration, and a newly developed stochastic model of cell migration in 3D matrices, to simulate the migration of cell clusters in different physiologically relevant environments. Our results show that based on the extracellular environment and the strength of cell–cell mechanical coupling, two distinct optimal approaches to driving collective cell migration emerge. The ability to effectively employ these two distinct migration strategies might be critical for cells to collectively migrate through the heterogeneous tissue environments within the body.
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This work was supported by Grants from the National Science Foundation (BMMB - 1905390, BMMB - 1763132 to P. K.) and the Army Research Office (W911NF-17-1-0413 to P. K.).
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Figure S1. Mean Squared Displacement (MSD) Plots for Example Cells at 1.25x10-3 fibers/\(\mu m^3\) . A) MSD plot on a log–log scale for low alignment and low cell–cell adhesion. Fit equations are shown in the same color as their plot, with goodness of fit given by R. Solid blue line is defined leader and solid red line is undefined leader. Colored dashed lines are the fits for their matching color. Dashed black line is \(\langle R^2\rangle = \tau\). B) MSD plot on a log–log scale for high alignment and low cell–cell adhesion. C) MSD plot on a log–log scale for low alignment and high cell–cell adhesion. D) MSD plot on a log–log scale for high alignment and high cell–cell adhesion (png 294 KB)
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Figure S2. Mean Squared Displacement (MSD) Plots for Example Cells at 1.63x10-3 fibers/\(\mu m^3\) . A) MSD plot on a log–log scale for low alignment and low cell–cell adhesion. Fit equations are shown in the same color as their plot, with goodness of fit given by R. Solid blue line is defined leader and solid red line is undefined leader. Colored dashed lines are the fits for their matching color. Dashed black line is \(\langle R^2\rangle = \tau\). B) MSD plot on a log–log scale for high alignment and low cell–cell adhesion. C) MSD plot on a log–log scale for low alignment and high cell–cell adhesion. D) MSD plot on a log–log scale for high alignment and high cell–cell adhesion (png 293 KB)
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Figure S3. This figure shows MSD results for 5-cell cluster over increasing fiber density. Figure S1 (a), (c), and (e) shows MSD with no fiber alignment, and Figure S1 (b), (d), and (f) shows MSD for clusters with high fiber alignment. Figure S1 (a) and (b) shows MSD with clusters at low adhesion (25 nN), Figure S1 (c) and (d) shows MSD at medium adhesion (50 nN), and Figure S1 (e) and (f) shows MSD at high adhesion (100 nN) (png 761 KB)
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Figure S4. This figure shows MSD results for 10-cell cluster over increasing fiber density. Figure S2 (a), (c), and (e) shows MSD with no fiber alignment, and Figure S2 (b), (d), and (f) shows MSD for clusters with high fiber alignment. Figure S2 (a) and (b) shows MSD with clusters at low adhesion (25 nN), Figure S2 (c) and (d) shows MSD at medium adhesion (50 nN), and Figure S2 (e) and (f) shows MSD at high adhesion (100 nN) (png 732 KB)
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Figure S5. Cluster Size vs. Lifetime for Defined and Undefined Leading Clusters. A) Defined leader cluster lifetime as a function of cluster size. B) Undefined leader cluster as a function of cluster size. Clusters were simulated with low adhesion (25 nN) in unaligned matrices. Error bars are mean squared error (png 128 KB)
Video S1 shows the migration of a 10-cell cluster with a single defined leader over 18 hours. This sample was run with high adhesion, no fiber alignment, and an intermediate fiber density. The cell color at each time step corresponds to the phases accordingly: contraction (green), outgrowth (yellow), and retraction (red) (mp4 5948 KB)
Video S2 shows the migration of a 10-cell cluster with an undefined leader over 38 hours. This sample was run with high adhesion, no fiber alignment, and an intermediate fiber density. The color at each time step corresponds to the phases accordingly: contraction (green), outgrowth (yellow), and retraction (red) (mp4 1590 KB)
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Collins, T.A., Yeoman, B.M. & Katira, P. To lead or to herd: optimal strategies for 3D collective migration of cell clusters. Biomech Model Mechanobiol 19, 1551–1564 (2020). https://doi.org/10.1007/s10237-020-01290-y
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DOI: https://doi.org/10.1007/s10237-020-01290-y