Optimal mechanical interactions direct multicellular network formation on elastic substrates.

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.

Optimal foraging strategies for mutually avoiding competitors.

Many animals are known to exhibit foraging patterns where the distances they travel in a given direction are drawn from a heavy-tailed Lévy distribution. Previous studies have shown that, under sparse and random resource conditions, solitary non-destructive (with regenerating resources) foragers perform a maximally efficient search with Lévy exponent µ equal to 2, while for destructive foragers, efficiency decreases with µ monotonically and there is no optimal µ. However, in nature, there also exist situations where multiple foragers, displaying avoidance behavior, interact with each other competitively. To understand the effects of such competition, we develop a stochastic agent-based simulation that models competitive foraging among mutually avoiding individuals by incorporating an avoidance zone, or territory, of a certain size around each forager which is not accessible for foraging by other competitors. For non-destructive foraging, our results show that with increasing size of the territory and number of agents the optimal Lévy exponent is still approximately 2 while the overall efficiency of the search decreases. At low values of the Lévy exponent, however, increasing territory size actually increases efficiency. For destructive foraging, we show that certain kinds of avoidance can lead to qualitatively different behavior from solitary foraging, such as the existence of an optimal search with 1<µ<2. Finally, we show that the variance among the efficiencies of the agents increases with increasing Lévy exponent for both solitary and competing foragers, suggesting that reducing variance might be a selective pressure for foragers adopting lower values of µ. Taken together, our results suggest that, for multiple foragers, mutual avoidance and efficiency variance among individuals can lead to optimal Lévy searches with exponents different from those for solitary foragers.