Detecting long-range interactions between migrating cells

C Metzner,C Mark,T Czerwinski,F Hörsch,C Voskens,A Winterl,B Fabry

doi:10.1038/s41598-021-94458-0

Abstract

Chemotaxis enables cells to systematically approach distant targets that emit a diffusible guiding substance. However, the visual observation of an encounter between a cell and a target does not necessarily indicate the presence of a chemotactic approach mechanism, as even a blindly migrating cell can come across a target by chance. To distinguish between the chemotactic approach and blind migration, we present an objective method that is based on the analysis of time-lapse recorded cell migration trajectories: For each movement step of a cell relative to the position of a potential target, we compute a p value that quantifies the likelihood of the movement direction under the null-hypothesis of blind migration. The resulting distribution of p values, pooled over all recorded cell trajectories, is then compared to an ensemble of reference distributions in which the positions of targets are randomized. First, we validate our method with simulated data, demonstrating that it reliably detects the presence or absence of remote cell-cell interactions. In a second step, we apply the method to data from three-dimensional collagen gels, interspersed with highly migratory natural killer (NK) cells that were derived from two different human donors. We find for one of the donors an attractive interaction between the NK cells, pointing to a cooperative behavior of these immune cells. When adding nearly stationary K562 tumor cells to the system, we find a repulsive interaction between K562 and NK cells for one of the donors. By contrast, we find attractive interactions between NK cells and an IL-15-secreting variant of K562 tumor cells. We therefore speculate that NK cells find wild-type tumor cells only by chance, but are programmed to leave a target quickly after a close encounter. We provide a freely available Python implementation of our p value method that can serve as a general tool for detecting long-range interactions in collective systems of self-driven agents.

Highlights

Chemotaxis enables cells to systematically approach distant targets that emit a diffusible guiding substance
The interpretation of the preceding phase, in which the natural killer (NK) cells approach their targets, is ambiguous: On the one hand, it is known that NK cells can show a chemotactic response to suitable chemokine gradients[4,5], and that they can be chemotactically recruited by other cells of the immune system that have located a p athogen[6,7]
In the RMS scenario, the overall shape of the p value distribution is different from the blind search’ (BLS) case, because RMS is a heterogeneous random walk

Summary

Introduction

Chemotaxis enables cells to systematically approach distant targets that emit a diffusible guiding substance. The situation is ambiguous in the case of micro-organisms, which can only migrate with a relatively large degree of directional randomness[2], and for which chemotaxis is often the only available mechanism to locate distant targets[3] We have encountered such ambiguous behavior in experiments with highly mobile natural killer (NK) cells and almost immobile tumor cells, randomly distributed inside a 3-dimensional collagen gel (for details see below). Computing the distribution of p values over all recorded immune cells and time steps reveals the presence of long-range interactions between immune cells and targets by a statistically significantly larger fraction of small p values compared to a reference distribution of p values in which the positions of the targets are randomized (Fig. 1c)

Methods

Results

Conclusion