Cytoskeletal mechanics in collective cell migration

Main text

Collective cell migration is a fundamental biological process that drives diverse physiological and pathological events, including embryonic development, wound healing, and cancer progression (1,2,3). A hallmark of this behavior is the ability of individual cells to dynamically rearrange within a cohesive tissue, a property strongly shaped by factors such as cell density, cell shape, and the physical constraints imposed by extracellular matrix (4,5,6). Recently, a power-law relationship of the wave frequency to the local cell density in spreading collective cells (4) and a density-dependent jamming transition in epithelial monolayers from fluid-like to solid-like behavior (5) have been demonstrated. In addition, it has become clear that the cell shape, quantified by the ratio of cell perimeter to the square root of the cell area, plays a dominant role in governing these transitions (6). While the intercellular adhesion and the chemo-mechanical feedback of actomyosin contraction (7,8) are known to regulate cell shape, emerging evidence highlights the crucial role of cell-substrate interactions, particularly the traction forces, generated by F-actin networks in coordinating collective motion (9). Yet, how the cytoskeletal mechanics, especially the dynamic behavior of F-actin, regulate collective migration across scales remains an open question.

In this issue of Biophysical Journal, Kong et al. (10) significantly advance our understanding of collective cell migration by turning the focus inward—onto the cytoskeletal reorganization of individual cells within an epithelial monolayer. Based on earlier experimental observations, they developed a vertex-based theoretical model that integrates two critical F-actin structures: stress fibers and cryptic lamellipodia (Figure 1). Within this framework, both the organization of F-actin and the resulting traction forces dynamically evolve in response to each cell’s internal stress state and interactions with neighboring cells. This approach enables the authors to dissect how subcellular mechanics shape emergent tissue-scale behaviors, effectively bridging the long-standing gap between intracellular cytoskeletal mechanics and collective migration.

Figure 1.

Cytoskeletal dynamics regulates collective cell migration

Through systematic simulations, Kong et al. (10) uncover how the stress fibers reshape cellular morphology to tune the fluidity and rearrangement frequency of dense epithelial monolayers. Strikingly, their model predicts that the strengthened stress fibers not only promote tissue unjamming but also boost the spatial coordination of traction forces, steering collective migration into a more cohesive and directed mode. Their study also shines a spotlight on the often-overlooked cryptic lamellipodia, subtle basal F-actin protrusions that subtly shape collective dynamics. Kong et al. (10) reveal its dual role: while longer cryptic lamellipodia extensions tend to disrupt coherent movement, the alignment of these structures across neighboring cells reinforces directional coordination. These insights offer a compelling explanation for the spatial heterogeneity observed during wound healing (11), where front-line and interior cells exhibit strikingly different migratory behaviors.

While the model necessarily simplifies certain aspects of F-actin dynamics, such as assuming a direct relationship between stress fiber abundance and principal stress or treating fiber tension as linearly dependent on cell shape, it nonetheless distills key biomechanical principles with remarkable clarity. Crucially, it generates testable predictions that could steer future experimental investigations. Extending this framework to more complex biological contexts promises to deepen our understanding of cytoskeletal regulation in morphogenesis, tissue repair, and other dynamic processes.

In summary, the work of Kong et al. (10) offers a compelling theoretical framework that bridges intracellular cytoskeletal mechanics with tissue-scale collective migration. By shifting the focus from external cues to the micromechanics within individual cells, they underscore the pivotal role of cytoskeletal dynamics in driving emergent collective behaviors. Their work opens new avenues for understanding how intracellular forces shape complex biological processes, from development and wound healing to cancer invasion.

Declaration of interests

The author declares no competing interests.

Editor: Baohua Ji.