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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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Wave of coordination of DA3 tumor cells.The wound healing process was divided into three phases [29]: Phase 1 – free front propagation until first contact between cells from the opposing fronts of the wound. Phase 2 – front matching until full closure of the voids. Phase 3 – post wound closure. (A) Visualization of the wave of coordination during the 3 phases of the healing process: cell clusters migrating with coordinated trajectories are overlaid on the initial time frame of each healing phase. Raw zoomed-in images of each healing phase are found below. (B–C) Waves of coordination for control (B) and HGF/SF-treated (C) cells. Histograms of coordination, measured by the fraction of cells that move in coordinated clusters, in relation to the distance from the edge, accumulated over all experiments. For all following analysis only Phase 1 is considered. (D–G) Spatiotemporal wave of coordination. Coordination was measured in high temporal resolution by clustering a grid of short (72.5 minutes or 5 frames long) trajectories using the same clustering algorithm as in (B–C). The average coordination at time (t) and distance (d) from the wound edge is shown in color code for every bin (t,d) in the map. (D) and (F): spatiotemporal maps (kymographs) for control (D) and HGF/SF-treated (F) cells. In both cases a wave of coordination is observed, and is significantly amplified as a response to HGF/SF treatment. (E) and (G): the average coordination for four 100-minute time intervals of the spatiotemporal maps (D) and (F) respectively. Different time is due to variance in initial wound width and healing rate.
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pcbi-1003747-g002: Wave of coordination of DA3 tumor cells.The wound healing process was divided into three phases [29]: Phase 1 – free front propagation until first contact between cells from the opposing fronts of the wound. Phase 2 – front matching until full closure of the voids. Phase 3 – post wound closure. (A) Visualization of the wave of coordination during the 3 phases of the healing process: cell clusters migrating with coordinated trajectories are overlaid on the initial time frame of each healing phase. Raw zoomed-in images of each healing phase are found below. (B–C) Waves of coordination for control (B) and HGF/SF-treated (C) cells. Histograms of coordination, measured by the fraction of cells that move in coordinated clusters, in relation to the distance from the edge, accumulated over all experiments. For all following analysis only Phase 1 is considered. (D–G) Spatiotemporal wave of coordination. Coordination was measured in high temporal resolution by clustering a grid of short (72.5 minutes or 5 frames long) trajectories using the same clustering algorithm as in (B–C). The average coordination at time (t) and distance (d) from the wound edge is shown in color code for every bin (t,d) in the map. (D) and (F): spatiotemporal maps (kymographs) for control (D) and HGF/SF-treated (F) cells. In both cases a wave of coordination is observed, and is significantly amplified as a response to HGF/SF treatment. (E) and (G): the average coordination for four 100-minute time intervals of the spatiotemporal maps (D) and (F) respectively. Different time is due to variance in initial wound width and healing rate.

Mentions: Clusters were identified using a specially designed segmentation algorithm that groups adjacent trajectories based on their similarity (Supporting Text SI4 in Text S1). This analysis was used to explicitly detect and quantify groups of cells that maintain their mutual coordination for several hours (Fig. 2A), allowing long and informative trajectories at the cost of low temporal resolution. Quantifying coordination over long trajectories was the only analysis that required processing the full wound healing process. All following analyses focus solely on the initial stage of free front propagation until first contact occurs between cells from the opposing fronts of the wound, as local properties are perturbed when contact occurs.


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)

Wave of coordination of DA3 tumor cells.The wound healing process was divided into three phases [29]: Phase 1 – free front propagation until first contact between cells from the opposing fronts of the wound. Phase 2 – front matching until full closure of the voids. Phase 3 – post wound closure. (A) Visualization of the wave of coordination during the 3 phases of the healing process: cell clusters migrating with coordinated trajectories are overlaid on the initial time frame of each healing phase. Raw zoomed-in images of each healing phase are found below. (B–C) Waves of coordination for control (B) and HGF/SF-treated (C) cells. Histograms of coordination, measured by the fraction of cells that move in coordinated clusters, in relation to the distance from the edge, accumulated over all experiments. For all following analysis only Phase 1 is considered. (D–G) Spatiotemporal wave of coordination. Coordination was measured in high temporal resolution by clustering a grid of short (72.5 minutes or 5 frames long) trajectories using the same clustering algorithm as in (B–C). The average coordination at time (t) and distance (d) from the wound edge is shown in color code for every bin (t,d) in the map. (D) and (F): spatiotemporal maps (kymographs) for control (D) and HGF/SF-treated (F) cells. In both cases a wave of coordination is observed, and is significantly amplified as a response to HGF/SF treatment. (E) and (G): the average coordination for four 100-minute time intervals of the spatiotemporal maps (D) and (F) respectively. Different time is due to variance in initial wound width and healing rate.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g002: Wave of coordination of DA3 tumor cells.The wound healing process was divided into three phases [29]: Phase 1 – free front propagation until first contact between cells from the opposing fronts of the wound. Phase 2 – front matching until full closure of the voids. Phase 3 – post wound closure. (A) Visualization of the wave of coordination during the 3 phases of the healing process: cell clusters migrating with coordinated trajectories are overlaid on the initial time frame of each healing phase. Raw zoomed-in images of each healing phase are found below. (B–C) Waves of coordination for control (B) and HGF/SF-treated (C) cells. Histograms of coordination, measured by the fraction of cells that move in coordinated clusters, in relation to the distance from the edge, accumulated over all experiments. For all following analysis only Phase 1 is considered. (D–G) Spatiotemporal wave of coordination. Coordination was measured in high temporal resolution by clustering a grid of short (72.5 minutes or 5 frames long) trajectories using the same clustering algorithm as in (B–C). The average coordination at time (t) and distance (d) from the wound edge is shown in color code for every bin (t,d) in the map. (D) and (F): spatiotemporal maps (kymographs) for control (D) and HGF/SF-treated (F) cells. In both cases a wave of coordination is observed, and is significantly amplified as a response to HGF/SF treatment. (E) and (G): the average coordination for four 100-minute time intervals of the spatiotemporal maps (D) and (F) respectively. Different time is due to variance in initial wound width and healing rate.
Mentions: Clusters were identified using a specially designed segmentation algorithm that groups adjacent trajectories based on their similarity (Supporting Text SI4 in Text S1). This analysis was used to explicitly detect and quantify groups of cells that maintain their mutual coordination for several hours (Fig. 2A), allowing long and informative trajectories at the cost of low temporal resolution. Quantifying coordination over long trajectories was the only analysis that required processing the full wound healing process. All following analyses focus solely on the initial stage of free front propagation until first contact occurs between cells from the opposing fronts of the wound, as local properties are perturbed when contact occurs.

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