New paradigms in the establishment and maintenance of gradients during directed cell migration

Abstract

Directional guidance of migrating cells is relatively well explored in the reductionist setting of cell culture experiments. Here spatial gradients of chemical cues as well as gradients of mechanical substrate characteristics prove sufficient to attract single cells as well as their collectives. How such gradients present and act in the context of an organism is far less clear. Here we review recent advances in understanding how guidance cues emerge and operate in complex physiological settings.

Figure 1. Modes of chemical gradient formation

A. Simple diffusion. In this mode, the spreading of particles occurs through free diffusion in the absence of cells or other hindrances. The mean squared displacement of particles (shown in green) is proportional to the diffusivity of the particles. Inset. At any given time, the concentration of the chemoattractant decays (broken line) logarithmically as a function of the distance from the source (green circle). B. Hindered diffusion. Short acting gradients are formed when particles encounter geometric obstacle or are sequestered or immobilized through the presence of sinks (shown in red). Inset. A rapid decay in chemoattractant concentration as a function of the distance from the source is observed compared to simple diffusion. Although molecules have high local diffusivities, their effective global diffusivity is low. C. Facilitated diffusion. The enhancement of chemoattractant diffusivity by a ‘positive regulator”. A positive regulator of diffusion (marked in blue) may be achieved via the transport of chemoattractants through cells (transcytosis), along cell extensions (cytonemes), by packaging into vesicles (exosomes) or any other form that prevents interactions that may otherwise hinder particle movement. Inset. The chemoattractant gradient shape is determined by the positive regulator and may not follow a logarithmic decay profile. D. Complex diffusion. Complex chemoattractant gradient pattern may be obtained when two or more gradients interact with each other. For example, periodic gradient patterns (Inset) may be obtained in a situation where a diffusing chemoattractant (green) encounters a gradient of a degradative enzyme (red), the production of which depends upon the concentration of the chemoattractant itself.

Figure 2. Gradient formation in cellular environments

A. Cells acting as sinks. Receptors expressed either on the migrating cells or in surrounding tissues may sequester or internalize chemoattractants, resulting in the establishment of gradients. Preferential expression of these sequestering “sink” receptors at the back or the front of migrating cells may result in a self-generated gradient. B. Signal relay by chemotaxing cells. Cells may produce a secondary chemoattractant in response to a freely diffusing primary chemoattractant. This secondary chemoattractant subsequently diffuses to recruit more cells, enhancing the sensitivity and robustness of the chemotaxis process. C. Mechanical gradients. Cells demonstrate directed migration under various mechanical cues. Durotaxis is the directed migration of cells or group of cells from a softer to a stiffer substrate. Haptotaxis is the migration of cells towards immobilized gradients of chemoattractant trapped by extracellular substrates. D. Gradients formed by small highly diffusible molecules. Gradients of small highly diffusible molecules may be created by a graded expression of a synthesizing enzyme. For example, the injured zebrafish epithelia produces H₂O₂ by a graded expression of NADPH oxidase, with higher expression in cells with higher degrees of injury.