Propagating Waves of Directionality and Coordination Orchestrate Collective Cell Migration

Abstract

The ability of cells to coordinately migrate in groups is crucial to enable them to travel long distances during embryonic development, wound healing and tumorigenesis, but the fundamental mechanisms underlying intercellular coordination during collective cell migration remain elusive despite considerable research efforts. A novel analytical framework is introduced here to explicitly detect and quantify cell clusters that move coordinately in a monolayer. The analysis combines and associates vast amount of spatiotemporal data across multiple experiments into transparent quantitative measures to report the emergence of new modes of organized behavior during collective migration of tumor and epithelial cells in wound healing assays. First, we discovered the emergence of a wave of coordinated migration propagating backward from the wound front, which reflects formation of clusters of coordinately migrating cells that are generated further away from the wound edge and disintegrate close to the advancing front. This wave emerges in both normal and tumor cells, and is amplified by Met activation with hepatocyte growth factor/scatter factor. Second, Met activation was found to induce coinciding waves of cellular acceleration and stretching, which in turn trigger the emergence of a backward propagating wave of directional migration with about an hour phase lag. Assessments of the relations between the waves revealed that amplified coordinated migration is associated with the emergence of directional migration. Taken together, our data and simplified modeling-based assessments suggest that increased velocity leads to enhanced coordination: higher motility arises due to acceleration and stretching that seems to increase directionality by temporarily diminishing the velocity components orthogonal to the direction defined by the monolayer geometry. Spatial and temporal accumulation of directionality thus defines coordination. The findings offer new insight and suggest a basic cellular mechanism for long-term cell guidance and intercellular communication during collective cell migration.

Modeling the finger instability in an expanding cell monolayer

“…When the positive feedback is too weak due to overall low cell motility (case 3), we again do not predict finger formation, as is indeed observed experimentally (Fig.7). Another feature that has been observed in several experiments, mostly when fingers do not form (as in case 2), is of waves of acceleration that propagate from the monolayer edge into the bulk [34,37,38]. We find somewhat similar waves in our system (Fig.S14), although a detailed study of this phenomenon is beyond the scope of this paper.…”

“…This is indeed observed for fast migrating cell layers [37]. When the positive feedback is too weak due to overall low cell motility (case 3), we again do not predict finger formation, as is indeed observed experimentally (Fig.7).…”

Vimentin Intermediate Filaments Template Microtubule Networks to Enhance Persistence in Cell Polarity and Directed Migration

“…The speed was defined as the magnitude of the local motion vector. The directionality was defined as the absolute value of the ratio between the two components (Zaritsky et al, 2014). Higher values reflect a local motion towards the wound edge while smaller values denote significant sideways motion.…”

Asymmetry in traction forces produced by migrating preadipocytes is bounded to 33%

“…Cell migration occurs either collectively, in groups or monolayers [12] , as in embryonic development [13] , or as single cells. Single cells may, for example extravasate through a blood vessel or cross tissue layers to reach a target location where they may differentiate and form tissues and organs [14,15] .…”