In recent years, the role of mechanical forces in cellular movement has been a central area of investigation within the field of mechanobiology. The long-standing assumption in cell biology has been that cells require high amounts of force to navigate their environment, overcome resistance, and migrate efficiently. However, a breakthrough study by researchers at the McKelvey School of Engineering at Washington University in St. Louis, led by Amit Pathak, a professor in mechanical engineering and materials science, challenges this established theory. This groundbreaking research reveals that cells can move more quickly on softer surfaces with aligned collagen fibers, despite generating and utilizing lower forces than previously thought necessary for fast migration.
For years, scientists have assumed that cellular migration relies heavily on the ability of cells to exert force in order to overcome friction and drag in their environment. As cells move, they push or pull on their surrounding extracellular matrix, a complex network of proteins and fibers, and generate mechanical force. In return, this force is resisted by the surface to which the cells are adhered, creating friction that cells must overcome. But according to the recent study, this dynamic might not be as straightforward as scientists once believed.
Amit Pathak and his team focused their research on the migration patterns of groups of human mammary epithelial cells, which have been a model system for studying cellular movement. Over the years, Pathak’s lab has made crucial observations that showed that cells on rigid, hard surfaces typically move faster than on softer, more compliant ones. On soft surfaces, the cells were found to stall and struggle with migration, seemingly hindered by the softness and lack of rigidity. In light of these previous findings, the new results have upended the understanding of how cellular migration is tied to force generation and environmental factors.
The new research, published in PLOS Computational Biology, demonstrates that cells move significantly faster on soft surfaces with aligned collagen fibers, compared to random fibers, even while generating lower forces. This revelation has far-reaching implications for understanding not only basic cell behavior but also the processes of cancer metastasis, wound healing, and tissue regeneration.
What makes this discovery truly surprising is the mechanism behind it. Unlike what one might expect from conventional wisdom, where friction is considered a key challenge that forces must overcome for movement, aligned collagen fibers seem to decrease friction in such a way that the cells can continue migrating more rapidly without needing to exert higher forces. The organization and alignment of collagen fibers play a critical role in guiding cellular movement and ensuring that cells follow a directed path, much like railroad tracks that guide a train along a designated route.
Pathak and his team’s study found that the aligned fibers acted as directional cues for the migrating cells, effectively guiding their movement and promoting collective migration. These cells, when placed on aligned collagen fibers, organized into groups that moved in the same direction. It was as if the aligned fibers served as physical tracks, providing both structural and directional guidance, aiding the cells in navigating their environment.
Amit Pathak elaborated on the surprising finding: “We wondered if you apply a force, and there’s no friction, can the cells keep going fast without generating more force?” This question led the researchers to explore how the environment influences cellular behavior. The traditional assumption was that friction or resistance in the environment must be overcome by cellular forces. However, the team was surprised to discover that the cells generated much less force while still managing to migrate faster. The findings suggested that cell migration is not purely about overcoming friction but rather about interacting with and utilizing the environment in more complex ways than originally expected.
The research team’s breakthrough was not just empirical but also theoretical. Amrit Bagchi, who earned a doctoral degree in mechanical engineering from the McKelvey School of Engineering in 2022 and was a key contributor to the study, developed a new model to explain the observed phenomenon. Bagchi’s research involved creating a soft hydrogel during the COVID-19 pandemic in collaboration with Marcus Foston, an associate professor of energy, environmental, and chemical engineering. The hydrogel served as a compliant surface that replicated soft tissues, while aligned collagen fibers were placed onto this hydrogel using a custom-designed magnet in the School of Medicine’s lab.
The experimental setup allowed the researchers to study the interaction of cells with this environment in real-time. Bagchi and the team wanted to investigate how force generation could be decoupled from cellular movement and how the cells could still travel at faster speeds on a softer surface with aligned collagen fibers. To explain the observed results, Bagchi proposed a multi-layered motor-clutch model, where the motor represented the force-generating mechanisms within the cell, and the clutch was the system providing traction and anchoring for the cells. This model incorporated three layers—cells, collagen fibers, and the hydrogel—working together to produce the observed phenomenon of faster migration despite lower forces.
As the study’s authors observed, aligned fibers may serve as proxies for a lack of friction in the way that traditional surfaces would provide it, but the cells’ response to the aligned environment differed significantly from what would occur in random fiber conditions. Bagchi explained, “Although the experimental results initially surprised us, they provided the impetus to develop a theoretical model to explain the physics behind this counterintuitive behavior.” His model, called “matrix mechanosensing and transmission,” now offers a robust framework for understanding how cells sense and respond to the surrounding environment.
The implications of this research extend far beyond mere curiosity about how cells move. The ability of cells to move faster on soft, aligned surfaces is essential to understanding various biological processes. For example, during cancer metastasis, cancer cells must migrate from the primary tumor site to distant organs, a process that is often guided by changes in the extracellular matrix and the surrounding microenvironment. The findings of this study could potentially reveal novel approaches to inhibit cancer metastasis by altering the mechanical properties of tissue environments.
Similarly, wound healing relies on cells migrating to the site of injury to close the wound and repair damaged tissues. Understanding how cells respond to mechanical cues, like the alignment of collagen fibers, could enhance the development of therapeutic strategies for more efficient healing. In tissue engineering and regenerative medicine, leveraging these insights might help design scaffolds and biomaterials that provide better guidance for cellular migration and growth.
Furthermore, the study holds potential for refining approaches to tissue regeneration. In the context of engineering complex tissues, aligned scaffolds that guide cell migration can be incorporated into therapeutic solutions that support the regeneration of damaged tissues. This holds profound implications for advancing clinical applications, such as reconstructive surgery, organ regeneration, and biomaterials science.
Pathak’s team’s findings also lay the groundwork for studying a wide range of migration behaviors beyond collective cell movement, including haptotaxis (movement toward a surface with higher adhesive strength) and durotaxis (movement in response to stiffness gradients). The new theoretical model developed by Bagchi and his colleagues offers a unified framework for analyzing these behaviors in a way that can be generalized across different types of cell migration phenomena.
As we continue to deepen our understanding of mechanobiology, it’s becoming clear that the environment plays an unexpectedly complex role in shaping cell behavior. Rather than simply acting as passive obstacles that cells must push against, environmental factors, like matrix alignment and fiber organization, can actively influence the direction, speed, and force of cellular migration. The work at Washington University demonstrates that softer, aligned environments may enable faster cell movement without the need for increased force, thus reversing previous assumptions about the role of forces in migration. This revelation invites scientists to rethink their models of cellular mechanics and opens up new avenues for both basic research and therapeutic interventions across a wide range of fields.
Reference: Amrit Bagchi et al, Fast yet force-effective mode of supracellular collective cell migration due to extracellular force transmission, PLOS Computational Biology (2025). DOI: 10.1371/journal.pcbi.1012664