ABOVE: Small clusters of cells migrated faster if they adopted a train-like formation and moved in single file. ©istock, jarcosa
Many cells in the body are on the move. This includes singular immune cells that audit tissue in pursuit of invading microbes as well as large groups of progenitor cells in the embryo that reshape the developing organism.1,2 Biophysicists have explored the locomotion of single cells and large masses grown in culture, but they know little about the migratory dynamics of smaller clusters of cells.3,4
In a recent Nature Physics publication, scientists studied how the shape of a small group of cells affects the efficiency of their transport.5 These findings lay the groundwork to understand how cells rideshare around the body, including cancer cells undergoing metastasis.
Sylvain Gabriele, a cell mechanobiologist at the University of Mons and study coauthor, studies cells on the move using custom-built, in vitro systems for guiding cell motion.
To explore the relationship between shape and migration efficiency, Gabriele and his team developed a 2D platform lined with rows of fibronectin—a glycoprotein that cells like to “walk” along.6 In this setup, cells moved along channels formed between rows of fibronectin. Specifically, Gabriele and his team tracked the movements of fish epidermal cells, which have a proclivity to migrate quickly.7 By varying the distance between parallel fibronectin tracks, Gabriele and his colleagues could fine-tune the thickness of cellular clusters.
They started with a small, 15-micrometer-wide gap that forced the epithelial cells to move single file. In this setup, the cells adhered to each other like train carriages and chugged along as a single unit. The team compared cellular trains that naturally varied from two to 18 compartments and measured their speed through the fibronectin system.
“At the beginning, we expected that the larger the cell train, the higher the velocity,” Gabriele said. He reasoned that because cells bunch up in a train formation, they form more contacts with each other and fewer with the platform in between the fibronectin tracks, reducing friction. However, Gabriele added, “We were very surprised to see that these long cell trains can have exactly the same velocity as single cells, regardless of the number of cells in the train.”
The team wondered how quickly epithelial cells would move if they allowed them to bunch up, so they widened the space between the fibronectin tracks to 30, 45, or 100 micrometers. The wider the gap, the thicker the cell cluster that formed and the slower the cells moved. The thickest clusters moved eight times slower than cellular trains, revealing that linear arrays of cells conserve more energy for transport.
The researchers modeled how sideways interactions between cells in the cluster affected the overall speed of the collective. “The energy which is used to maintain cell-cell contacts comes at the expense of energy which is available to move the cells forward,” Gabriele said. Cells lose energy when they adhere to each other and push and pull at their neighbors, creating internal stresses that use up energy, he added. Cellular trains, on the other hand, form fewer attachments, propelling the cells to travel faster.
Going beyond fish epidermal cells, the team still needs to determine if human cells, such as metastasizing breast cancer cells, adopt the train formation to migrate around the body faster. “If you look in the breast, [there are] very highly aligned collagen fibers that can be used as a track in order to disseminate tumor cells,” Gabriele said.
Mathieu Dedenon, a biophysicist at the University of Geneva who was not involved with the work, praised the researchers’ decision to use theoretical models to support the experimental data. He would like to see additional experiments performed that use more complex surfaces to recapitulate the polymer-laden obstacle courses found inside body tissues and the developing embryo. “During development you have a specific extracellular matrix on which cells migrate, and sometimes you have an underlying layer of cells,” Dedenon said. “It will change the adhesion and the steepness felt by cells, and so I think it would be a natural continuation where you can study collective migration in more physiological environments.”
References
1. Worbs T, et al. Dendritic cell migration in health and disease. Nat Rev Immunol. 2017;17(1):30-48.
2. Marchant CL, et al. Cell clusters softening triggers collective cell migration in vivo. Nat Mater. 2022;21(11):1314-1323.
3. Mak M, et al. Single-cell migration in complex microenvironments: Mechanics and signaling dynamics. J Biomech Eng. 2016;138(2):021004.
4. Serra-Picamal X, et al. Mechanical waves during tissue expansion. Nat Phys. 2012;8(8):628-634.
5. Vercruysse E, et al. Geometry-driven migration efficiency of autonomous epithelial cell clusters. Nat Phys. 2024:1-9.
6. Vedula SRK, et al. Emerging modes of collective cell migration induced by geometrical constraints. Proc Natl Acad Sci USA. 2012;109(32):12974-12979.
7. Riaz M, et al. Persistence of fan-shaped keratocytes is a matrix-rigidity-dependent mechanism that requires α5β1 integrin engagement. Sci Rep. 2016;6(1):34141.