Self-Generated Gradients Yield Exceptionally Robust Steering Cues

Abstract

Chemotaxis is a widespread mechanism that allows migrating cells to steer to where they are needed. Attractant gradients may be imposed by external sources, or selfgenerated, when cells create their own steep local gradients by breaking down a prevalent, broadly distributed attractant. Here we show that chemotaxis works far more robustly toward self-generated gradients. Cells can only respond efficiently to a restricted range of attractant concentrations; if attractants are too dilute, their gradients are too shallow for cells to sense, but if they are too high, all receptors become saturated and cells cannot perceive spatial differences. Self-generated gradients are robust because cells maintain the attractant at optimal concentrations. A wave can recruit varying numbers of steered cells, and cells can take time to break down attractant before starting to migrate. Self-generated gradients can therefore operate over a greater range of attractant concentrations, larger distances, and longer times than imposed gradients. The robustness is further enhanced at low cell numbers if attractants also act as mitogens, and at high attractant concentrations if the enzymes that break down attractants are themselves induced by constant attractant levels.

Hypoxia triggers collective aerotactic migration in Dictyostelium discoideum

“…Both of these behaviors could be very important to help Dd cells to navigate complex hypoxic environments they encounter in the soil. In addition, our results are a confirmation of the ability of self-generated gradients to serve as very robust, long-lasting directional cues in environmental navigation, a property which has recently emerged in a variety of systems ( Cremer et al, 2019 ; Tweedy and Insall, 2020 ). Finally, our work goes beyond theses results as it demonstrates that oxygen can play the role of the attractant in self-generated gradients therefore potentially extending the physiological relevance of the use of such cues in collective migration.…”

“…Indeed, the original experiments of Adler ( Adler, 1966 ) and more recent developments ( Cremer et al, 2019 ; Fu et al, 2018 ; Saragosti et al, 2011 ) on bacteria demonstrated that similar ingredients as the ones presented here can lead to front propagation in both 1d and 2d situations. Similarly, using an under agarose assay, it was demonstrated that self-generated gradients of degraded folate induce a group migration of cells in bands (in 1D) or rings (in 2D spots) up to 4 mm ( Tweedy and Insall, 2020 ). Beyond the dimensionality of the system, it was also shown that self-generated gradients allow cells to solve mazes by locally degrading an attractant that has a source at the exit of the maze ( Tweedy et al, 2020 ).…”

“…The self-generated LPA (melanoma) and folate ( Dd ) gradients were modeled with a simple numerical model that was able to predict the steady wave. In particular, it predicted an invasive front where cells are exposed to a steep chemoattractant gradient, followed by a ‘trailing end’ where the gradient is shallow and fewer cells migrate with poor directionality ( Tweedy and Insall, 2020 ). It also predicted that the wave may have a less marked front, and/or a smaller speed, or even vanishes if the cell density was too low due to insufficient chemoattractant removal.…”

“…The mechanism is simple and very robust: the cell colony acts as a sink for the chemoattractant, removes it by degradation or uptake creating a gradient that, in turn, attracts the cells as long as the chemoattractant is present in the environment. Physiologically speaking, self-generated gradients have been demonstrated to increase the range of expansion of cell colonies ( Cremer et al, 2019 ; Tweedy and Insall, 2020 ) and to serve as directional cues to help various cell types navigate complex environments, including mazes ( Tweedy et al, 2020 ). Recently, it was demonstrated that after covering an epithelial cell colony by a coverglass non permeable to O 2 , peripheral cells exhibit a strong outward directional migration to escape hypoxia from the center of the colony ( Deygas et al, 2018 ).…”

Hypoxia triggers collective aerotactic migration inDictyostelium discoideum

“…The self-generated LPA (melanoma) and folate ( Dd ) gradients were modeled with a simple numerical model that was able to predict the steady wave. In particular, it predicted an invasive front where cells are exposed to a steep chemoattractant gradient, followed by a ‘trailing end’ where the gradient is shallow and fewer cells migrate with poor directionality(Tweedy & Insall, 2020). It also predicted that the wave may have a less marked front, and/or a smaller speed, or even vanishes if the cell density was too low due to insufficient chemoattractant removal.…”