Sequential coupling of phases in unjamming transition of epithelial cells via spatiotemporal analysis on physical phenotypes

Changes in cellular phenotypes are noticeable traits of various pathophysiological events, including cancer metastasis, morphogenesis, and tissue regeneration. For instance, epithelial cells undergo distinct phenotypic transitions known as jamming and unjamming, which correspond to the cessation and awakening of the cell motility, respectively. When epithelial cells become crowded, the pack of cells is halted and maintains the hexagonal shape resulting in a well-designed barrier function. In contrast, the jammed epithelial cells regain motile functions when the cell is exposed to external cues such as growth factors, physical pressure, and empty spaces. Especially, cell migration, a key component for processing pathophysiological situations, requires the unjamming transition (UJT) as a prerequisite. While many researchers have investigated UJT recently, UJT remains largely unexplored. Here, we attempt to induce the UJT of the normal breast epithelial cell line (MCF 10A) by introducing the empty spaces after the cells are densely jammed. The MCF10A monolayer encounters the spaces, cells near the boundary initiate migration toward the empty region and transmits the migratory behavior to the posterior cells. If the cells are simply assumed to be linked particles, the migration transmission will occur gradually. However, the migration of cells in the rear part is formed at a certain time and location. To clarify the intriguing transition in the cellular motility of follower cells, we spatiotemporally quantify physical characteristics, including traction force, intercellular stress, and morphology of constituent cells. The extensive analysis on correlations between physical variables suggests that the UJT of epithelial cells begins with the accumulation of intercellular stress and completes with the cell division-driven relaxation of stress. In conclusion, this study successively proposes the integrated mechanism of UJT, that inclusively involves cell division, traction force, and cellular morphology.