Accuracy of Chemotactic Response to Transient Gradient Signals Studied in Silico

Chemotaxis, the oriented migration of cells guided by chemical gradients, is a fundamental biological process important in embryogenesis, wound healing, immune system function and canc! er meta a mathematical model for a novel experimental protocol exploiting fast switching in a microfluidics device to challenge chemotactic cells with transient gradient signals. Our intracellular in silico cell model falls in the broad class of local excitation / global inhibition (LEGI) models in which G-protein coupled receptor activation events initiate both local excitatory signaling cascades (e.g. promoting pseudopod formation) and global inhibition via release of a rapidly diffusing inhibitory signal (e.g. suppressing pseudopod formation). Our implementation includes fluctuations due to the discrete nature of the signal release and diffusion processes within the small volume of a living cell. These stochastic effects limit the accuracy of individual cells' responses to a given gradient signal, consistent with experimental observations of migrating cell tracks in microfluidics devices. Within this framework we ask how accurately a cell can in! fer the ly presented gradient signal as a function of (i) the duration of the signal, (ii) the relative gradient steepness and mean signaling molecule concentration, and (iii) the ambient background concentration before the gradient is introduced. Limits on the accuracy of cell movement are derived from numerical experiments and are quantified in terms of both the circular variance of the cellular compass (also known as the chemotactic index) and in terms of the statistical entropy or mutual information of the ensemble of cell responses.