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Propagating waves of directionality and coordination orchestrate collective cell migration.

Zaritsky A, Kaplan D, Hecht I, Natan S, Wolf L, Gov NS, Ben-Jacob E, Tsarfaty I - PLoS Comput. Biol. (2014)

Bottom Line: 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.Spatial and temporal accumulation of directionality thus defines coordination.

View Article: PubMed Central - PubMed

Affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.

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.

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HGF/SF-induced wave of directionality.(A, C) Spatiotemporal maps (kymographs) of the average directionality of DA3 tumor cells, in response to HGF/SF treatment (C), in comparison with the control results (A). The x-axis represents the time measured in minutes and the y-axis represents the distance from the wound edge in microns (see the text and Figure 2). (B, D) The average directionality for four 100-minute time intervals of the spatiotemporal maps in (A) and (C), respectively. (E–F) HGF/SF enhances persistent migration of DA3 cells. (E) Average persistent migration as function of distance from the wound edge, with and without HGF/SF. In response to HGF/SF, cells migrate with higher persistence. Each treatment plot was composed of 3,000–4,000 distinct trajectories extracted throughout Phase 1. (F) Full distributions of trajectories' persistence, accumulated over all experiments.
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pcbi-1003747-g004: HGF/SF-induced wave of directionality.(A, C) Spatiotemporal maps (kymographs) of the average directionality of DA3 tumor cells, in response to HGF/SF treatment (C), in comparison with the control results (A). The x-axis represents the time measured in minutes and the y-axis represents the distance from the wound edge in microns (see the text and Figure 2). (B, D) The average directionality for four 100-minute time intervals of the spatiotemporal maps in (A) and (C), respectively. (E–F) HGF/SF enhances persistent migration of DA3 cells. (E) Average persistent migration as function of distance from the wound edge, with and without HGF/SF. In response to HGF/SF, cells migrate with higher persistence. Each treatment plot was composed of 3,000–4,000 distinct trajectories extracted throughout Phase 1. (F) Full distributions of trajectories' persistence, accumulated over all experiments.

Mentions: A wave of enhanced directionality emerges following the HGF/SF-induced wave of acceleration and stretching. Here the directionality is measured for each layer at a distance (d) at each time (t) from the wound edge by - the ratio between the average speed towards the wound edge and the average speed in the parallel direction. More specifically, and are the average perpendicular speed and the average of the absolute value of the parallel speed, respectively, of all the agents that belong to a layer at distance (d) and at time (t). Note that since cells do not move backward from the wound edge, . Figures 4A and 4C show kymographs of this directionality measure for DA3 cells. Consecutive time projections (columns) of the spatiotemporal maps further illustrate the wave-like dynamics of the directionality in response to HGF/SF (Figs. 4B and 4D). Comparison between the collective migration in response to HGF/SF and the control reveals that the directionality wave is generated as a response to HGF/SF treatment.


Propagating waves of directionality and coordination orchestrate collective cell migration.

Zaritsky A, Kaplan D, Hecht I, Natan S, Wolf L, Gov NS, Ben-Jacob E, Tsarfaty I - PLoS Comput. Biol. (2014)

HGF/SF-induced wave of directionality.(A, C) Spatiotemporal maps (kymographs) of the average directionality of DA3 tumor cells, in response to HGF/SF treatment (C), in comparison with the control results (A). The x-axis represents the time measured in minutes and the y-axis represents the distance from the wound edge in microns (see the text and Figure 2). (B, D) The average directionality for four 100-minute time intervals of the spatiotemporal maps in (A) and (C), respectively. (E–F) HGF/SF enhances persistent migration of DA3 cells. (E) Average persistent migration as function of distance from the wound edge, with and without HGF/SF. In response to HGF/SF, cells migrate with higher persistence. Each treatment plot was composed of 3,000–4,000 distinct trajectories extracted throughout Phase 1. (F) Full distributions of trajectories' persistence, accumulated over all experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4109844&req=5

pcbi-1003747-g004: HGF/SF-induced wave of directionality.(A, C) Spatiotemporal maps (kymographs) of the average directionality of DA3 tumor cells, in response to HGF/SF treatment (C), in comparison with the control results (A). The x-axis represents the time measured in minutes and the y-axis represents the distance from the wound edge in microns (see the text and Figure 2). (B, D) The average directionality for four 100-minute time intervals of the spatiotemporal maps in (A) and (C), respectively. (E–F) HGF/SF enhances persistent migration of DA3 cells. (E) Average persistent migration as function of distance from the wound edge, with and without HGF/SF. In response to HGF/SF, cells migrate with higher persistence. Each treatment plot was composed of 3,000–4,000 distinct trajectories extracted throughout Phase 1. (F) Full distributions of trajectories' persistence, accumulated over all experiments.
Mentions: A wave of enhanced directionality emerges following the HGF/SF-induced wave of acceleration and stretching. Here the directionality is measured for each layer at a distance (d) at each time (t) from the wound edge by - the ratio between the average speed towards the wound edge and the average speed in the parallel direction. More specifically, and are the average perpendicular speed and the average of the absolute value of the parallel speed, respectively, of all the agents that belong to a layer at distance (d) and at time (t). Note that since cells do not move backward from the wound edge, . Figures 4A and 4C show kymographs of this directionality measure for DA3 cells. Consecutive time projections (columns) of the spatiotemporal maps further illustrate the wave-like dynamics of the directionality in response to HGF/SF (Figs. 4B and 4D). Comparison between the collective migration in response to HGF/SF and the control reveals that the directionality wave is generated as a response to HGF/SF treatment.

Bottom Line: 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.Spatial and temporal accumulation of directionality thus defines coordination.

View Article: PubMed Central - PubMed

Affiliation: Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv, Israel.

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.

Show MeSH
Related in: MedlinePlus