# Exosome-mediated chemotaxis optimizes leader-follower cell migration

## TL;DR

Cells use exosomes to communicate during migration, and optimal communication happens when exosomes are of intermediate size.

## Contribution

The study reveals that exosome size affects migration efficiency by balancing signal frequency and strength.

## Key findings

- Exosome-mediated chemotactic velocity depends non-monotonically on exosome cargo size.
- Intermediate exosome size maximizes information throughput for follower cell migration.
- Memory integration and secretion rate determine optimal cargo size for effective signaling.

## Abstract

Cells frequently employ extracellular vesicles, or exosomes, to signal across long distances and coordinate collective actions. Exosomes diffuse slowly, can be actively degraded, and contain stochastic amounts of molecular cargo. These features raise the question of the efficacy of exosomes as a directional signal, but this question has not be systematically investigated. We develop a theoretical and computational approach to quantify the limits of exosome-mediated chemotaxis at the individual cell level. In our model, a leader cell secretes exosomes, which diffuse in the extracellular space, and a follower cell guides its migration by integrating discrete exosome detections over a finite memory window. We combine analytical calculations and stochastic simulations and show that the chemotactic velocity exhibits a non-monotonic dependence on the exosome cargo size. Small exosomes produce frequent but weak signals, whereas large exosomes produce strong but infrequent encounters. In the presence of nonlinear signal transduction, this tradeoff leads to an optimal cargo size that maximizes information throughput, as quantified by the average speed of the follower cell. Using a reduced one-dimensional model, we derive closed-form expressions coupling the optimal cargo size to follower speed as a function of secretion rate, memory time, and detection sensitivity. These results identify molecular packaging and memory integration as key determinants of exosome-mediated information transmission and highlight general design principles for optimization of migration under guidance by discrete and diffusible signaling particles.

For cells to be capable of performing essential activities as collectives and clusters, they must be capable of communicating with each other efficiently. One way they do this is by releasing nanoparticles, known as exosomes, that transport cargos of signaling molecules. Unlike free molecules secreted directly from the cell, which diffuse continuously and widely, exosomes diffuse slowly, degrade over time, and contain random amounts of cargo. How do cells make reliable decisions from such noisy and intermittent information? In this study, we employed mathematical modeling and computational simulations to explore how a follower cell can faithfully track a leader cell by utilizing exosomes secreted from the latter. We found that, for a follower cell to move more reliably, exosomes ought to be of intermediate size. Too small and they transmit little information. Too large and they are released too infrequently. This balance suggests a general principle by which cells can bundle information in order to communicate effectively.