Enhanced chemotaxis through spatially regulated absolute concentration robustness

Abstract

Chemotaxis, the directional motility of cells in response to spatial gradients of chemical cues, is a fundamental process behind a wide range of biological events, including the innate immune response and cancer metastasis. Recent advances in cell biology have shown that the protrusions that enable amoeboid cells to move are driven by the stochastic threshold crossings of an underlying excitable system. As a cell encounters a chemoattractant gradient, the size of this threshold is regulated spatially so that the crossings are biased toward the front of the cell. For efficient directional migration, cells must limit undesirable lateral and rear-directed protrusions. The inclusion of a control mechanism to suppress these unwanted firings would enhance chemotactic efficiency. It is known that absolute concentration robustness (ACR) exerts tight control over the mean and variance of species concentration. Here, we demonstrate how the coupling of the ACR mechanism to the cellular signaling machinery reduces the likelihood of threshold crossings in the excitable system. Moreover, we show that using the cell's innate gradient sensing apparatus to direct the action of ACR to the rear suppresses the lateral movement of the cells and that this results in improved chemotactic performance.

The emergence of a collective sensory response threshold in ant colonies

“…Mechanistically, thresholds in biological systems almost always emerge from a balance between two opposing forces: exciting and restoring electrical currents in excitable membranes ( 9 ), excitatory and inhibitory neurons in neural networks ( 10 ), or interregion connections at the level of the entire brain ( 11 ). Similar dynamical phenomena are also abundant in nonneural systems such as the immune system, cellular and microorganismal behavior, or intracellular signaling networks ( 12 – 15 ).…”

Balancing at the edge of excitability: Implications for cell movement

“…Through a technique known as absolute concentration robustness (ACR) [37], the stochastic fluctuations of a biochemical network can be reduced. If this is done in a spatially-dependent manner so that the rear of the cell has smaller fluctuations and hence fewer firings, chemotactic efficiency is also improved [27]. Interestingly, we found that the ACR motif that would accomplish this is similar to some of the cell's signaling network, suggesting the possibility that the cell is already using some form of ACR.…”

“…The cells started at origin and the final positions are denoted with red circles. The viscoelastic model parameters are as in [27]. narrow region of space:…”

“…To determine the effect of these firings on cell chemotaxis, we followed an approach that simulates the movement of cells using a center-of-mass approximation [27]. Using the spatially-depended level of activity, shown in Fig.…”

Waves in a Stochastic Cell Motility Model

“…This implies that an external signal does not necessarily activate the dynamics at a certain point on the membrane, but rather changes the random walk of the cell into a biased random walk in the direction of the signal. Using a more extended model than presented here, it is shown in [2] that coupling an external signal to the stochastic dynamics of the cell indeed can lead to movement in the direction of that signal.…”