Cells discovered that move through the body like ‘trains on a track’

When you look under the microscope, a group of cells slowly moves forward in a line, like a train on the track. The cells navigate through complex environments. A new approach by researchers involving the Institute of Science and Technology Austria (ISTA) now shows how they do this and how they interact with each other. The experimental observations and the following mathematical concept have been published in Natural physics.

The majority of cells in the human body cannot move. However, some specific ones may go to different places. For example, in wound healing, cells move through the body to repair damaged tissue. They sometimes travel alone or in different group sizes. Although the process is increasingly understood, little is known about how cells interact with each other during travel and how they collectively navigate the complex environments in the body. An interdisciplinary team of theoretical physicists from the Institute of Science and Technology Austria (ISTA) and experimental researchers from the University of Bergen in Belgium now have new insights.

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Similar to experiments in social dynamics, where understanding the interactions of a small group of people is easier than analyzing an entire society, the scientists studied the travel behavior of a small group of cells in well-defined in vitro environment, that is, outside a living organism, in a petri dish provided with interior features. Based on their findings, they developed a framework of interaction rules, which is now published in Natural physics.

Cells travel on trains

David Brückner rushes back to his office to grab his laptop. “I think it would be better to show some videos of our experiments,” he says excitedly and presses play.

The video shows a petri dish. Microstripes – one-dimensional strips that guide cell movement – ​​are printed on the substrate next to a zebrafish scale composed of numerous cells. Special wound-healing cells known as ‘keratocytes’ begin to extend from the shell and form branches in the orbits. “Initially, cells stick together through adhesive molecules on their surfaces – it’s like holding hands,” explains Brückner. Suddenly the bond is broken and the cells gather into small groups, moving along tracks like trains. “The length of the train is always different. Sometimes there are two, sometimes there are ten. It depends on the initial conditions.”

Eléonore Vercurysse and Sylvain Gabriele from the University of Mons in Belgium observed this phenomenon while investigating keratocytes and their wound healing characteristics within different geometric patterns. To help interpret these puzzling observations, they contacted theoretical physicists David Brückner and Edouard Hannezo from ISTA.

Cells have a handlebar

“There is a gradient within each cell that determines where the cell goes. It’s called ‘polarity’ and it’s like the steering wheel of the cell itself,” says Brückner. “Cells communicate their polarity to neighboring cells, allowing them to move together.” But how they do that has remained a major puzzle in the field.

Brückner and Hannezo started brainstorming. The two scientists developed a mathematical model that combines a cell’s polarity, their interactions and the geometry of their environment. They then transferred the framework to computer simulations, allowing them to visualize different scenarios.

The first thing the scientists in Austria looked at was the speed of the cell trains. The simulation showed that the speed of the trains is independent of their length, whether they consist of two or ten cells. “Imagine if the first cell did all the work and dragged the others behind it; overall performance would decrease,” says Hannezo. “But that is not the case. Within the trains, all cells are polarized in the same direction. They are aligned and in sync with their movements and move forward smoothly.” In other words, the trains operate as four-wheel drive instead of just front-wheel drive.

As a next step, the theorists examined in their simulations the effects of increasing the width of the lanes and the cell clusters. Compared to cells moving in single file, clusters were much slower. The explanation is quite simple: the more cells are clustered together, the more they bump into each other. These collisions cause them to polarize away from each other and move in opposite directions. The cells are misaligned, which disrupts the flow of motion and drastically affects overall speed. This phenomenon was also observed in the Belgian laboratory (in vitro experiments).

Dead end? No problem for cell clusters

From an efficiency perspective, it sounds like moving in clusters is not ideal. However, the model predicted that there would also be benefits when cells navigate complex terrain, as they do in the human body, for example. To test this, the scientists added a dead end both in the experiments and in the simulations.

“Trains of cells quickly reach a dead end, but have difficulty changing direction. Their polarization is well aligned, and it is very difficult for them to agree on a switch,” says Brückner. “While in the cluster a large number of cells are already polarized in the other direction, making the change of direction much easier.”

Trains or clusters?

Naturally, the question arises: when do cells move in clusters, and when do they move in trains? The answer is that both scenarios occur in nature. For example, some developmental processes depend on clusters of cells moving from one side to the other, while others depend on small trains of cells moving independently of each other. “Our model does not only apply to one process. Instead, it is a broadly applicable framework that shows that placing cells in an environment with geometric constraints is highly educational, as it challenges them and allows us to decipher their interactions with each other,” Hannezo adds.

A train full of information

Recent publications from the Hannezo group suggest that cell communication propagates in waves: an interaction between biochemical signals, physical behavior and movement. The scientists’ new model now provides a physical basis for these cell-to-cell interactions, potentially helping to understand the big picture. Based on this framework, collaborators can delve deeper into the molecular players involved in this process. According to Brückner, the behavior revealed by these small cell trains can help us understand large-scale movements, such as those in whole tissues.

Reference: Vercruysse E, Brückner DB, Gómez-González M, et al. Geometry-driven migration efficiency of autonomous epithelial cell clusters. Nat Phys. 2024. doi: 10.1038/s41567-024-02532-x

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