Many types of animal cells exert active, contractile forces and mechanically deform their elastic substrate, to accomplish biological functions such as migration. These substrate deformations provide a mechanism in principle by which cells may sense other cells, leading to long-range mechanical inter–cell interactions and possible self-organization. Here, inspired by cell mechanobiology, we propose an active matter model comprising self-propelling particles that interact at a distance through their mutual deformations of an elastic substrate. By combining a minimal model for the motility of individual particles with a linear elastic model that accounts for substrate-mediated, inter–particle interactions, we examine emergent collective states that result from the interplay of motility and long-range elastic dipolar interactions. In particular, we show that particles self-assemble into flexible, motile chains which can cluster to form diverse larger-scale compact structures with polar order. By computing key structural and dynamical metrics, we distinguish between the collective states at weak and strong elastic interaction strength, as well as at low and high motility. We also show how these states are affected by confinement within a channel geometry–an important characteristic of the complex mechanical micro-environment inhabited by cells. Our model predictions may be generally applicable to active matter with dipolar interactions ranging from biological cells to synthetic colloids endowed with electric or magnetic dipole moments.
more »
« less
Matrix Stiffness Modulates Mechanical Interactions and Promotes Contact between Motile Cells
The mechanical micro-environment of cells and tissues influences key aspects of cell structure and function, including cell motility. For proper tissue development, cells need to migrate, interact, and form contacts. Cells are known to exert contractile forces on underlying soft substrates and sense deformations in them. Here, we propose and analyze a minimal biophysical model for cell migration and long-range cell–cell interactions through mutual mechanical deformations of the substrate. We compute key metrics of cell motile behavior, such as the number of cell-cell contacts over a given time, the dispersion of cell trajectories, and the probability of permanent cell contact, and analyze how these depend on a cell motility parameter and substrate stiffness. Our results elucidate how cells may sense each other mechanically and generate coordinated movements and provide an extensible framework to further address both mechanical and short-range biophysical interactions.
more »
« less
- PAR ID:
- 10291547
- Date Published:
- Journal Name:
- Biomedicines
- Volume:
- 9
- Issue:
- 4
- ISSN:
- 2227-9059
- Page Range / eLocation ID:
- 428
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Cell development and behavior are driven by internal genetic programming, but the external microenvironment is increasingly recognized as a significant factor in cell differentiation, migration, and in the case of cancer, metastatic progression. Yet it remains unclear how the microenvironment influences cell processes, especially when examining cell motility. One factor that affects cell motility is cell mechanics, which is known to be related to substrate stiffness. Examining how cells interact with each other in response to mechanically differential substrates would allow an increased understanding of their coordinated cell motility. In order to probe the effect of substrate stiffness on tumor related cells in greater detail, we created hard–soft–hard (HSH) polydimethylsiloxane (PDMS) substrates with alternating regions of different stiffness (200 and 800 kPa). We then cultured WI-38 fibroblasts and A549 epithelial cells to probe their motile response to the substrates. We found that when the 2 cell types were exposed simultaneously to the same substrate, fibroblasts moved at an increased speed over epithelial cells. Furthermore, the HSH substrate allowed us to physically guide and separate the different cell types based on their relative motile speed. We believe that this method and results will be important in a diversity of areas including mechanical microenvironment, cell motility, and cancer biology.more » « less
-
Adhesive cell–substrate interactions are crucial for cell motility and are responsible for the necessary traction that propels cells. These interactions can also change the shape of the cell, analogous to liquid droplet wetting on adhesive substrates. To address how these shape changes affect cell migration and cell speed we model motility using deformable, 2D cross-sections of cells in which adhesion and frictional forces between cell and substrate can be varied separately. Our simulations show that increasing the adhesion results in increased spreading of cells and larger cell speeds. We propose an analytical model which shows that the cell speed is inversely proportional to an effective height of the cell and that increasing this height results in increased internal shear stress. The numerical and analytical results are confirmed in experiments on motile eukaryotic cells.more » « less
-
Cells self-organize into functional, ordered structures during tissue morphogenesis, a process that is evocative of colloidal self-assembly into engineered soft materials. Understanding how intercellular mechanical interactions may drive the formation of ordered and functional multicellular structures is important in developmental biology and tissue engineering. Here, by combining an agent-based model for contractile cells on elastic substrates with endothelial cell culture experiments, we show that substrate deformation–mediated mechanical interactions between cells can cluster and align them into branched networks. Motivated by the structure and function of vasculogenic networks, we predict how measures of network connectivity like percolation probability and fractal dimension as well as local morphological features including junctions, branches, and rings depend on cell contractility and density and on substrate elastic properties including stiffness and compressibility. We predict and confirm with experiments that cell network formation is substrate stiffness dependent, being optimal at intermediate stiffness. We also show the agreement between experimental data and predicted cell cluster types by mapping a combined phase diagram in cell density substrate stiffness. Overall, we show that long-range, mechanical interactions provide an optimal and general strategy for multicellular self-organization, leading to more robust and efficient realizations of space-spanning networks than through just local intercellular interactions.more » « less
-
Tullman-Ercek, Danielle (Ed.)ABSTRACT A wide range of biological systems, from microbial swarms to bird flocks, display emergent behaviors driven by coordinated movement of individuals. To this end, individual organisms interact by recognizing their kin and adjusting their motility based on others around them. However, even in the best-studied systems, the mechanistic basis of the interplay between kin recognition and motility coordination is not understood. Here, using a combination of experiments and mathematical modeling, we uncover the mechanism of an emergent social behavior in Myxococcus xanthus . By overexpressing the cell surface adhesins TraA and TraB, which are involved in kin recognition, large numbers of cells adhere to one another and form organized macroscopic circular aggregates that spin clockwise or counterclockwise. Mechanistically, TraAB adhesion results in sustained cell-cell contacts that trigger cells to suppress cell reversals, and circular aggregates form as the result of cells’ ability to follow their own cellular slime trails. Furthermore, our in silico simulations demonstrate a remarkable ability to predict self-organization patterns when phenotypically distinct strains are mixed. For example, defying naive expectations, both models and experiments found that strains engineered to overexpress different and incompatible TraAB adhesins nevertheless form mixed circular aggregates. Therefore, this work provides key mechanistic insights into M. xanthus social interactions and demonstrates how local cell contacts induce emergent collective behaviors by millions of cells. IMPORTANCE In many species, large populations exhibit emergent behaviors whereby all related individuals move in unison. For example, fish in schools can all dart in one direction simultaneously to avoid a predator. Currently, it is impossible to explain how such animals recognize kin through brain cognition and elicit such behaviors at a molecular level. However, microbes also recognize kin and exhibit emergent collective behaviors that are experimentally tractable. Here, using a model social bacterium, we engineer dispersed individuals to organize into synchronized collectives that create emergent patterns. With experimental and mathematical approaches, we explain how this occurs at both molecular and population levels. The results demonstrate how the combination of local physical interactions triggers intracellular signaling, which in turn leads to emergent behaviors on a population scale.more » « less