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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 waves of acceleration and stretching.(A–D) Spatiotemporal maps (kymographs) of acceleration (A and C) and strain rate (B and D), calculated for each agent as explained in the text and in Supporting Text SI4 in Text S1. The x-axis represents the time in minutes and the y-axis represents the distance from the wound edge in microns. Each element (t,d) in the map shows the average acceleration (in A and C) and strain rate (in B and D) measured at time (t) for all the agents of a layer of width Δd = 12.4 µm (10 pixels), located at a distance (d) from the wound edge, over a time interval Δt = 14.5 minutes (1 frame). (E) and (F): the average coordination for four 100-minute time intervals of the spatiotemporal maps in (C) and (D), respectively. These figures illustrate the highly coinciding waves of increasing motility (acceleration) and stretching (strain rate).
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pcbi-1003747-g003: HGF/SF-induced waves of acceleration and stretching.(A–D) Spatiotemporal maps (kymographs) of acceleration (A and C) and strain rate (B and D), calculated for each agent as explained in the text and in Supporting Text SI4 in Text S1. The x-axis represents the time in minutes and the y-axis represents the distance from the wound edge in microns. Each element (t,d) in the map shows the average acceleration (in A and C) and strain rate (in B and D) measured at time (t) for all the agents of a layer of width Δd = 12.4 µm (10 pixels), located at a distance (d) from the wound edge, over a time interval Δt = 14.5 minutes (1 frame). (E) and (F): the average coordination for four 100-minute time intervals of the spatiotemporal maps in (C) and (D), respectively. These figures illustrate the highly coinciding waves of increasing motility (acceleration) and stretching (strain rate).

Mentions: Figure 3 shows spatiotemporal maps (kymographs) of acceleration and strain rate for DA3 cells. Each element (t,d) in the map shows the average acceleration, over time interval Δt = 14.5 minutes (1 frame), (Figs. 3A and 3C) and the average strain rate (Figs. 3B and 3D), at time (t) for all the agents of a layer of width Δd = 12.4 µm (10 pixels), located at a distance (d) from the wound edge. Consecutive time projections (columns) of the spatiotemporal maps for HGF/SF treatment further illustrate the wave-like dynamics of the acceleration and strain rate (Figs. 3E and 3F). Comparison between the collective migration in response to HGF/SF and the control reveals that the wave of acceleration and stretching is generated as a response to HGF/SF treatment, while in the control case the acceleration and strain-rates spread from the edge inwards in a smooth manner without a distinct wave front. Comparison between the time projections of the spatiotemporal maps for acceleration (Fig. 3E) and strain rate (Fig. 3F) reveals the accurate coinciding of the waves of increasing motility (acceleration) and stretching (strain rate). These waves propagate at roughly twice the speed of the advancing front edge, consistently with previously published results [31].


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 waves of acceleration and stretching.(A–D) Spatiotemporal maps (kymographs) of acceleration (A and C) and strain rate (B and D), calculated for each agent as explained in the text and in Supporting Text SI4 in Text S1. The x-axis represents the time in minutes and the y-axis represents the distance from the wound edge in microns. Each element (t,d) in the map shows the average acceleration (in A and C) and strain rate (in B and D) measured at time (t) for all the agents of a layer of width Δd = 12.4 µm (10 pixels), located at a distance (d) from the wound edge, over a time interval Δt = 14.5 minutes (1 frame). (E) and (F): the average coordination for four 100-minute time intervals of the spatiotemporal maps in (C) and (D), respectively. These figures illustrate the highly coinciding waves of increasing motility (acceleration) and stretching (strain rate).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g003: HGF/SF-induced waves of acceleration and stretching.(A–D) Spatiotemporal maps (kymographs) of acceleration (A and C) and strain rate (B and D), calculated for each agent as explained in the text and in Supporting Text SI4 in Text S1. The x-axis represents the time in minutes and the y-axis represents the distance from the wound edge in microns. Each element (t,d) in the map shows the average acceleration (in A and C) and strain rate (in B and D) measured at time (t) for all the agents of a layer of width Δd = 12.4 µm (10 pixels), located at a distance (d) from the wound edge, over a time interval Δt = 14.5 minutes (1 frame). (E) and (F): the average coordination for four 100-minute time intervals of the spatiotemporal maps in (C) and (D), respectively. These figures illustrate the highly coinciding waves of increasing motility (acceleration) and stretching (strain rate).
Mentions: Figure 3 shows spatiotemporal maps (kymographs) of acceleration and strain rate for DA3 cells. Each element (t,d) in the map shows the average acceleration, over time interval Δt = 14.5 minutes (1 frame), (Figs. 3A and 3C) and the average strain rate (Figs. 3B and 3D), at time (t) for all the agents of a layer of width Δd = 12.4 µm (10 pixels), located at a distance (d) from the wound edge. Consecutive time projections (columns) of the spatiotemporal maps for HGF/SF treatment further illustrate the wave-like dynamics of the acceleration and strain rate (Figs. 3E and 3F). Comparison between the collective migration in response to HGF/SF and the control reveals that the wave of acceleration and stretching is generated as a response to HGF/SF treatment, while in the control case the acceleration and strain-rates spread from the edge inwards in a smooth manner without a distinct wave front. Comparison between the time projections of the spatiotemporal maps for acceleration (Fig. 3E) and strain rate (Fig. 3F) reveals the accurate coinciding of the waves of increasing motility (acceleration) and stretching (strain rate). These waves propagate at roughly twice the speed of the advancing front edge, consistently with previously published results [31].

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