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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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Association among the waves for DA3 tumor cells exposed to HGF/SF.(A, C): The association between the waves of acceleration and directionality; (B, D): the association between the waves of directionality and coordination. (A) Scatter plot comparison of directionality vs. acceleration. Each dot in a scatter plot represents an element (t,d) in the two corresponding spatiotemporal maps, accumulated over all the experimental replicates (N = 5). (B) Similar to (A) but for the coordination vs. directionality. (C) Cross correlation between acceleration and directionality. The graph shows the Pearson correlation for different time shifts computed between the spatiotemporal maps of acceleration and directionality accumulated for all the experiments. (D) Cross correlation between the spatiotemporal maps of directionality and coordination accumulated for all the experiments. Inset: cross correlation between a spatiotemporal map of directionality and coordination demonstrating about 30 minutes time shift for a specific experiment.
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pcbi-1003747-g006: Association among the waves for DA3 tumor cells exposed to HGF/SF.(A, C): The association between the waves of acceleration and directionality; (B, D): the association between the waves of directionality and coordination. (A) Scatter plot comparison of directionality vs. acceleration. Each dot in a scatter plot represents an element (t,d) in the two corresponding spatiotemporal maps, accumulated over all the experimental replicates (N = 5). (B) Similar to (A) but for the coordination vs. directionality. (C) Cross correlation between acceleration and directionality. The graph shows the Pearson correlation for different time shifts computed between the spatiotemporal maps of acceleration and directionality accumulated for all the experiments. (D) Cross correlation between the spatiotemporal maps of directionality and coordination accumulated for all the experiments. Inset: cross correlation between a spatiotemporal map of directionality and coordination demonstrating about 30 minutes time shift for a specific experiment.

Mentions: To address the hypothesis that strain rate and acceleration are associated with directionality we preformed spatiotemporal cross-correlation analysis between these properties as follows. Figure 6A shows a scatter plot of directionality vs. acceleration for DA3 cells exposed to HGF/SF. In general, each dot in the scatter plot represents an element (t,d) in the two corresponding spatiotemporal maps. Figure 6A corresponds to spatiotemporal maps such as the one shown in Fig. 3C (acceleration) and 4C (directionality). This scatter plot includes the results not only for a specific experiment but for all the maps of the N = 5 repetitions of the wound healing of DA3 cells in the presence of HGF/SF. The results show an overall trend of higher directionality for higher acceleration. Interestingly, after the wave moves on to backward layers, the directionality doesn't only decrease to a lower level, but decreases to a level that is similar to that of control cells (Fig. 5D, cyan line).


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)

Association among the waves for DA3 tumor cells exposed to HGF/SF.(A, C): The association between the waves of acceleration and directionality; (B, D): the association between the waves of directionality and coordination. (A) Scatter plot comparison of directionality vs. acceleration. Each dot in a scatter plot represents an element (t,d) in the two corresponding spatiotemporal maps, accumulated over all the experimental replicates (N = 5). (B) Similar to (A) but for the coordination vs. directionality. (C) Cross correlation between acceleration and directionality. The graph shows the Pearson correlation for different time shifts computed between the spatiotemporal maps of acceleration and directionality accumulated for all the experiments. (D) Cross correlation between the spatiotemporal maps of directionality and coordination accumulated for all the experiments. Inset: cross correlation between a spatiotemporal map of directionality and coordination demonstrating about 30 minutes time shift for a specific experiment.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g006: Association among the waves for DA3 tumor cells exposed to HGF/SF.(A, C): The association between the waves of acceleration and directionality; (B, D): the association between the waves of directionality and coordination. (A) Scatter plot comparison of directionality vs. acceleration. Each dot in a scatter plot represents an element (t,d) in the two corresponding spatiotemporal maps, accumulated over all the experimental replicates (N = 5). (B) Similar to (A) but for the coordination vs. directionality. (C) Cross correlation between acceleration and directionality. The graph shows the Pearson correlation for different time shifts computed between the spatiotemporal maps of acceleration and directionality accumulated for all the experiments. (D) Cross correlation between the spatiotemporal maps of directionality and coordination accumulated for all the experiments. Inset: cross correlation between a spatiotemporal map of directionality and coordination demonstrating about 30 minutes time shift for a specific experiment.
Mentions: To address the hypothesis that strain rate and acceleration are associated with directionality we preformed spatiotemporal cross-correlation analysis between these properties as follows. Figure 6A shows a scatter plot of directionality vs. acceleration for DA3 cells exposed to HGF/SF. In general, each dot in the scatter plot represents an element (t,d) in the two corresponding spatiotemporal maps. Figure 6A corresponds to spatiotemporal maps such as the one shown in Fig. 3C (acceleration) and 4C (directionality). This scatter plot includes the results not only for a specific experiment but for all the maps of the N = 5 repetitions of the wound healing of DA3 cells in the presence of HGF/SF. The results show an overall trend of higher directionality for higher acceleration. Interestingly, after the wave moves on to backward layers, the directionality doesn't only decrease to a lower level, but decreases to a level that is similar to that of control cells (Fig. 5D, cyan line).

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