Beyond Force: The Intricacies of Cell Migration

Within the realm of mechanobiology, the forces exerted by cells have been regarded as essential for their improved functionality, including rapid migration. Nonetheless, a team of investigators at the McKelvey School of Engineering at Washington University in St. Louis has discovered that cells can create and utilize lesser forces while moving faster than those producing and employing greater forces, thereby overturning a long-held belief regarding force.

Amit Pathak’s laboratory, where he serves as a professor of mechanical engineering and materials science, revealed that clusters of cells exhibited increased speed with lower force when attached to soft surfaces adorned with aligned collagen fibers. It has been assumed that cells must perpetually generate forces, as they need to surpass the friction and drag of their environment in order to progress. However, this traditional requirement for forces might be diminished in optimal environmental situations, like those involving aligned fibers.

The findings from the team, published in PLOS Computational Biology, are the first to demonstrate this behavior during collective cell migration.

Pathak and his lab associates have monitored the movement of human mammary epithelial cells over several years, discovering that cells travel at a higher speed on rigid, firm surfaces compared to softer surfaces where they tend to become stuck. Their investigations bear significant implications for cancer spread and wound recovery.

In this recent study, they observed that cells migrated over 50% quicker on aligned collagen fibers versus random fibers. Furthermore, they found that cells utilize aligned fibers as directional indicators to steer their migration towards expanding their populations.

“We questioned whether applying force, in the absence of friction, would allow cells to maintain their speed without needing to generate additional force,” said Pathak. “We understood that this likely depends on the environmental conditions. We anticipated that they would move faster on aligned fibers, akin to railroad tracks, but what was unexpected was their ability to generate lower forces while maintaining higher speeds.”

Amrit Bagchi, who obtained a doctorate in mechanical engineering from McKelvey Engineering in 2022 while working in Pathak’s lab and is currently a postdoctoral researcher at the Center for Engineering MechanoBiology at the University of Pennsylvania, dedicated considerable effort to establish the research.

Bagchi formulated a soft hydrogel in the laboratory of Marcus Foston, an associate professor of energy, environmental and chemical engineering, over several months during the COVID-19 pandemic. He then aligned the fibers with a specialized magnet at the School of Medicine before introducing the cells to observe their movements.

Bagchi devised a multi-layered motor-clutch model where the force-generating components within the cells act as the motor, while the clutch provides traction for the cells. He skillfully adapted this model for the collective cells using three layers—one for the cells, another for the collagen fibers, and one for the custom gel beneath—which all interacted with one another.

“Although the experimental outcomes caught us by surprise at first, they motivated us to create a theoretical framework to elucidate the physics underlying this seemingly paradoxical behavior,” Bagchi mentioned. “In time, we realized that cells interpret aligned fibers as a substitute for experiencing frictional forces in a manner that diverges significantly from the scenario involving random fibers.”

“Our model’s principle of matrix mechanosensing and transmission also forecasts other well-studied collective migration attributes, such as haptotaxis and durotaxis, providing a cohesive structure for researchers to investigate and potentially extend to other fascinating cell migration phenotypes.”