Interaction of Motility, Directional Sensing, and Polarity Modules Recreates the Behaviors of Chemotaxing Cells

Chemotaxis involves the coordinated action of separable but interrelated processes: motility, gradient sensing, and polarization. We have hypothesized that these are mediated by separate modules that account for these processes individually and that, when combined, recreate most of the behaviors of chemotactic cells. Here, we describe a mathematical model where the modules are implemented in terms of reaction-diffusion equations. Migration and the accompanying changes in cellular morphology are demonstrated in simulations using a mechanical model of the cell cortex implemented in the level set framework. The central module is an excitable network that accounts for random migration. The response to combinations of uniform stimuli and gradients is mediated by a local excitation, global inhibition module that biases the direction in which excitability is directed. A polarization module linked to the excitable network through the cytoskeleton allows unstimulated cells to move persistently and, for cells in gradients, to gradually acquire distinct sensitivity between front and back. Finally, by varying the strengths of various feedback loops in the model we obtain cellular behaviors that mirror those of genetically altered cell lines.Author Summary: Chemotaxis is the movement of cells in response to spatial gradients of chemical cues. While single-celled organisms rely on sensing and responding to chemical gradients to search for nutrients, chemotaxis is also an essential component of the mammalian immune system. However, chemotaxis can also be deleterious, since chemotactic tumor cells can lead to metastasis. Due to its importance, understanding the process by which cells sense and respond to chemical gradients has attracted considerable interest. Moreover, because of the complexity of chemotactic signaling, which includes multiple feedback loops and redundant pathways, this has been a research area in which computational models have had a significant impact in understanding experimental findings. Here, we propose a modular description of the signaling network that regulates chemotaxis. The modules describe different processes that are observed in chemotactic cells. In addition to accounting for these behaviors individually, we show that the overall system recreates many features of the directed motion of migrating cells. The signaling described by our modules is implemented as a series of equations, whereas movement and the accompanying cellular deformations are simulated using a mechanical model of the cell and implemented using level set methods, a method that allows simulations of cells as they change morphology.