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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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Waves in MDCK cells.Applying the same analysis and comparing the results to DA3 cells yielded similar directionality (A, C), and coordination (B, D) for the control case and in response to HGF/SF. (E) HGF/SF enhances persistent migration of MDCK cells (left – mean persistence as a function of the distance from the wound edge, right – full distribution of trajectories' persistent migration), accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F–G) Association between the waves, accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F) Acceleration and directionality, optimal delay was 217 minutes. Inset: association when considering the optimal delay. (G) Directionality and coordination. All phenomena observed in DA3 cells were evident also in MDCK cells, but with a lesser extent. We hypothesize that the tighter adhesions between MDCK cells [53] reduces the above mentioned phenomena by limiting efficient acceleration of cells in the wound's direction.
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pcbi-1003747-g007: Waves in MDCK cells.Applying the same analysis and comparing the results to DA3 cells yielded similar directionality (A, C), and coordination (B, D) for the control case and in response to HGF/SF. (E) HGF/SF enhances persistent migration of MDCK cells (left – mean persistence as a function of the distance from the wound edge, right – full distribution of trajectories' persistent migration), accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F–G) Association between the waves, accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F) Acceleration and directionality, optimal delay was 217 minutes. Inset: association when considering the optimal delay. (G) Directionality and coordination. All phenomena observed in DA3 cells were evident also in MDCK cells, but with a lesser extent. We hypothesize that the tighter adhesions between MDCK cells [53] reduces the above mentioned phenomena by limiting efficient acceleration of cells in the wound's direction.

Mentions: The waves described above and their associations also emerge, under the same conditions with striking similarity, during collective migration of MDCK epithelial cells (Fig. 7), the most common model system for 2D collective cell migration.


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)

Waves in MDCK cells.Applying the same analysis and comparing the results to DA3 cells yielded similar directionality (A, C), and coordination (B, D) for the control case and in response to HGF/SF. (E) HGF/SF enhances persistent migration of MDCK cells (left – mean persistence as a function of the distance from the wound edge, right – full distribution of trajectories' persistent migration), accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F–G) Association between the waves, accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F) Acceleration and directionality, optimal delay was 217 minutes. Inset: association when considering the optimal delay. (G) Directionality and coordination. All phenomena observed in DA3 cells were evident also in MDCK cells, but with a lesser extent. We hypothesize that the tighter adhesions between MDCK cells [53] reduces the above mentioned phenomena by limiting efficient acceleration of cells in the wound's direction.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g007: Waves in MDCK cells.Applying the same analysis and comparing the results to DA3 cells yielded similar directionality (A, C), and coordination (B, D) for the control case and in response to HGF/SF. (E) HGF/SF enhances persistent migration of MDCK cells (left – mean persistence as a function of the distance from the wound edge, right – full distribution of trajectories' persistent migration), accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F–G) Association between the waves, accumulated over all experiments (N = 5 for HGF/SF treated cells, N = 5 for control cells). (F) Acceleration and directionality, optimal delay was 217 minutes. Inset: association when considering the optimal delay. (G) Directionality and coordination. All phenomena observed in DA3 cells were evident also in MDCK cells, but with a lesser extent. We hypothesize that the tighter adhesions between MDCK cells [53] reduces the above mentioned phenomena by limiting efficient acceleration of cells in the wound's direction.
Mentions: The waves described above and their associations also emerge, under the same conditions with striking similarity, during collective migration of MDCK epithelial cells (Fig. 7), the most common model system for 2D collective cell migration.

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