Collective cell migration in 3D extracellular matrix (ECM) is crucial to many physiological and pathological processes. Migrating cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers and lead to a dynamically evolving force network in the system. Here, we elucidate the role of this force network in regulating collective cell behaviors using a minimal active-particle-on-network (APN) model, in which active particles can pull the fibers and hop between neighboring nodes of the network following local durotaxis. Our model reveals a dynamic transition as the particle number density approaches a critical value, from an “absorbing” state containing isolated stationary small particle clusters, to an “active” state containing a single large cluster undergoing constant dynamic reorganization. This reorganization is dominated by a subset of highly dynamic “radical” particles in the cluster, whose number also exhibits a transition at the same critical density. The transition is underlaid by the percolation of “influence spheres” due to the particle pulling forces. Our results suggest a robust mechanism based on ECM-mediated mechanical coupling for collective cell behaviors in 3D ECM.
more »
« less
Spatiotemporal force and motion in collective cell migration
Cells move in collective groups in biological processes such as wound healing, morphogenesis, and cancer metastasis. How active cell forces produce the motion in collective cell migration is still unclear. Many theoretical models have been introduced to elucidate the relationship between the cell’s active forces and different observations about the collective motion such as collective swirls, oscillations, and rearrangements. Though many models share the common feature of balancing forces in the cell layer, the specific relationships between force and motion vary among the different models, which can lead to different conclusions. Simultaneous experimental measurements of force and motion can aid in testing assumptions and predictions of the theoretical models. Here, we provide time-lapse images of cells in 1 mm circular islands, which are used to compute cell velocities, cell-substrate tractions, and monolayer stresses. Additional data are included from experiments that perturbed cell number density and actomyosin contractility. We expect this data set to be useful to researchers interested in force and motion in collective cell migration.
more » « less- Award ID(s):
- 1660703
- PAR ID:
- 10164405
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Data
- Volume:
- 7
- Issue:
- 1
- ISSN:
- 2052-4463
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
We have developed much understanding of actin-driven cell migration and the forces that propel cell motility. However, fewer studies focused on estimating the effective forces generated by migrating cells. Since cells in vivo are exposed to complex physical environments with various barriers, understanding the forces generated by cells will provide insights into how cells manage to navigate challenging environments. In this work, we use theoretical models to discuss actin-driven and water-driven cell migration and the effect of cell shapes on force generation. The results show that the effective force generated by actin-driven cell migration is proportional to the rate of actin polymerization and the strength of focal adhesion; the energy source comes from the actin polymerization against the actin network pressure. The effective force generated by water-driven cell migration is proportional to the rate of active solute flux and the coefficient of external hydraulic resistance; the energy sources come from active solute pumping against the solute concentration gradient. The model further predicts that the actin network distribution is mechanosensitive and the presence of globular actin helps to establish a biphasic cell velocity in the strength of focal adhesion. The cell velocity and effective force generation also depend on the cell shape through the intracellular actin flow field.more » « less
-
Living cells are out of equilibrium active materials. Cell-generated forces are transmitted across the cytoskeleton network and to the extracellular environment. These active force interactions shape cellular mechanical behavior, trigger mechano-sensing, regulate cell adaptation to the microenvironment and can affect disease outcomes. In recent years, the mechanobiology community has witnessed the emergence of many experimental and theoretical approaches to study cells as mechanically active materials. In this review, we highlight recent advancements in incorporating active characteristics of cellular behavior at different length scales into classic viscoelastic models by either adding an active tension-generating element or by adjusting the resting length of an elastic element in the model. Summarizing the two groups of approaches, we will review the formulation, and application of these models to understand cellular adaptation mechanisms in response to various types of mechanical stimuli, such as the effect of extracellular matrix properties and external loadings or deformations.more » « less
-
more » « less
Abstract Spatial patterning of different cell types is crucial for tissue engineering and is characterized by the formation of sharp boundary between segregated groups of cells of different lineages. The cell−cell boundary layers, depending on the relative adhesion forces, can result in kinks in the border, similar to fingering patterns between two viscous partially miscible fluids which can be characterized by its fractal dimension. This suggests that mathematical models used to analyze the fingering patterns can be applied to cell migration data as a metric for intercellular adhesion forces. In this study, we develop a novel computational analysis method to characterize the interactions between blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), which form segregated vasculature by recognizing each other through podoplanin. We observed indiscriminate mixing with LEC−LEC and BEC−BEC pairs and a sharp boundary between LEC−BEC pair, and fingering-like patterns with pseudo-LEC−BEC pairs. We found that the box counting method yields fractal dimension between 1 for sharp boundaries and 1.3 for indiscriminate mixing, and intermediate values for fingering-like boundaries. We further verify that these results are due to differential affinity by performing random walk simulations with differential attraction to nearby cells and generate similar migration pattern, confirming that higher differential attraction between different cell types result in lower fractal dimensions. We estimate the characteristic velocity and interfacial tension for our simulated and experimental data to show that the fractal dimension negatively correlates with capillary number (
Ca ), further indicating that the mathematical models used to study viscous fingering pattern can be used to characterize cell−cell mixing. Taken together, these results indicate that the fractal analysis of segregation boundaries can be used as a simple metric to estimate relative cell−cell adhesion forces between different cell types. -
more » « less
Abstract Background Collective cell migration underlies many essential processes, including sculpting organs during embryogenesis, wound healing in the adult, and metastasis of cancer cells. At mid-oogenesis,
Drosophila border cells undergo collective migration. Border cells round up into a small group at the pre-migration stage, detach from the epithelium and undergo a dynamic and highly regulated migration at the mid-migration stage, and stop at the oocyte, their final destination, at the post-migration stage. While specific genes that promote cell signaling, polarization of the cluster, formation of protrusions, and cell-cell adhesion are known to regulate border cell migration, there may be additional genes that promote these distinct active phases of border cell migration. Therefore, we sought to identify genes whose expression patterns changed during border cell migration.Results We performed RNA-sequencing on border cells isolated at pre-, mid-, and post-migration stages. We report that 1,729 transcripts, in nine co-expression gene clusters, are temporally and differentially expressed across the three migration stages. Gene ontology analyses and constructed protein-protein interaction networks identified genes expected to function in collective migration, such as regulators of the cytoskeleton, adhesion, and tissue morphogenesis, but also uncovered a notable enrichment of genes involved in immune signaling, ribosome biogenesis, and stress responses. Finally, we validated the in vivo expression and function of a subset of identified genes in border cells.
Conclusions Overall, our results identified differentially and temporally expressed genetic networks that may facilitate the efficient development and migration of border cells. The genes identified here represent a wealth of new candidates to investigate the molecular nature of dynamic collective cell migrations in developing tissues.
