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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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Related in: MedlinePlus

A simplified model to test the hypothesis that strain rate triggers cellular directional response.(A) A qualitative description by a simple model of the relations between velocity, acceleration, strain rate, and directionality. Simulated particle velocity in the direction of the wound V+(t) (solid purple line), acceleration (dashed line), and linker attachment probability in the direction of the wound ρ(t) (solid yellow line). (B) Strain rate triggers a directional response (model calculation). Calculated ratio of the directional velocity parallel (V∥) to the directional velocity toward The wound (V+) as the acceleration wave propagates, for increasing sharpness of the wave (decreasing σ in Supporting Text S1), corresponding to a wave that is either sharper or with same σ but with larger overall peak acceleration leading to higher final velocity. Both give higher strain-rate and higher directionality according to our proposed relation of directionality on linker occupation (purple curve versus yellow curve as control). (C–D) Experimental results: scatter plot comparison of directionality: V+ vs. V∥. Each dot in the scatter plot represents an element (t,d) in the two Corresponding spatiotemporal maps. The results presented here were accumulated over all available experiments (N = 5 for HGF/SF treated cells, N = 6 for control cells). HGF/SF-treated DA3 cells migrate in an enhanced directional manner (D), compared to control cells (C), similarly to the corresponding theoretical purple and yellow plot in (B). (E) Morphology of single DA3 cells as function of time and distance from the wound. Average cell area (left panel) and eccentricity (elongation, right panel) as function of time. Cells stretch to become larger and more elongated as the acceleration and strain-rate wave traverses the monolayer. When the wave passes to deeper cells, enhanced directionality is lost (B) theoretically, (C) and (D) experimentally), but the cells keep maintaining their elongated morphology. (F) Subjective single cells observations served as another indication for the validity of the experimental and theoretic results. Visualization of manual cell tracking (each cell marker with a different color) show that cells elongate to the direction of the wound edge followed by migration in a directional manner upon arrival of the waves. Time is in the format hh:mm. The corresponding video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/46351.
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pcbi-1003747-g005: A simplified model to test the hypothesis that strain rate triggers cellular directional response.(A) A qualitative description by a simple model of the relations between velocity, acceleration, strain rate, and directionality. Simulated particle velocity in the direction of the wound V+(t) (solid purple line), acceleration (dashed line), and linker attachment probability in the direction of the wound ρ(t) (solid yellow line). (B) Strain rate triggers a directional response (model calculation). Calculated ratio of the directional velocity parallel (V∥) to the directional velocity toward The wound (V+) as the acceleration wave propagates, for increasing sharpness of the wave (decreasing σ in Supporting Text S1), corresponding to a wave that is either sharper or with same σ but with larger overall peak acceleration leading to higher final velocity. Both give higher strain-rate and higher directionality according to our proposed relation of directionality on linker occupation (purple curve versus yellow curve as control). (C–D) Experimental results: scatter plot comparison of directionality: V+ vs. V∥. Each dot in the scatter plot represents an element (t,d) in the two Corresponding spatiotemporal maps. The results presented here were accumulated over all available experiments (N = 5 for HGF/SF treated cells, N = 6 for control cells). HGF/SF-treated DA3 cells migrate in an enhanced directional manner (D), compared to control cells (C), similarly to the corresponding theoretical purple and yellow plot in (B). (E) Morphology of single DA3 cells as function of time and distance from the wound. Average cell area (left panel) and eccentricity (elongation, right panel) as function of time. Cells stretch to become larger and more elongated as the acceleration and strain-rate wave traverses the monolayer. When the wave passes to deeper cells, enhanced directionality is lost (B) theoretically, (C) and (D) experimentally), but the cells keep maintaining their elongated morphology. (F) Subjective single cells observations served as another indication for the validity of the experimental and theoretic results. Visualization of manual cell tracking (each cell marker with a different color) show that cells elongate to the direction of the wound edge followed by migration in a directional manner upon arrival of the waves. Time is in the format hh:mm. The corresponding video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/46351.

Mentions: A simplified model was devised to test the hypothesis that strain rate (cellular stretching) leads to directional migration (See Supporting Text SI2 in Text S1). The cells were modeled as viscous elements which modify their shape in response to local stretching forces that are proportional to the strain-rate. The stretching forces associated with the acceleration wave can trigger a force-induced dissociation of cell-cell linkers in the direction of the stretch (i.e., towards the wound), thereby breaking the isotropy of the cell within the layer. This anisotropy is assumed to be trigger cell directionality: it can serve as a signal that recruits more actin-based motile machinery towards the wound compared to the orthogonal directions, creating a large velocity anisotropy ratio (Fig. 5). A simple linear relation between the stretch-induced linker anisotropy and the resulting velocity anisotropy ratio is assumed and gives good qualitative agreement with the experimental observations (Fig. 5).


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)

A simplified model to test the hypothesis that strain rate triggers cellular directional response.(A) A qualitative description by a simple model of the relations between velocity, acceleration, strain rate, and directionality. Simulated particle velocity in the direction of the wound V+(t) (solid purple line), acceleration (dashed line), and linker attachment probability in the direction of the wound ρ(t) (solid yellow line). (B) Strain rate triggers a directional response (model calculation). Calculated ratio of the directional velocity parallel (V∥) to the directional velocity toward The wound (V+) as the acceleration wave propagates, for increasing sharpness of the wave (decreasing σ in Supporting Text S1), corresponding to a wave that is either sharper or with same σ but with larger overall peak acceleration leading to higher final velocity. Both give higher strain-rate and higher directionality according to our proposed relation of directionality on linker occupation (purple curve versus yellow curve as control). (C–D) Experimental results: scatter plot comparison of directionality: V+ vs. V∥. Each dot in the scatter plot represents an element (t,d) in the two Corresponding spatiotemporal maps. The results presented here were accumulated over all available experiments (N = 5 for HGF/SF treated cells, N = 6 for control cells). HGF/SF-treated DA3 cells migrate in an enhanced directional manner (D), compared to control cells (C), similarly to the corresponding theoretical purple and yellow plot in (B). (E) Morphology of single DA3 cells as function of time and distance from the wound. Average cell area (left panel) and eccentricity (elongation, right panel) as function of time. Cells stretch to become larger and more elongated as the acceleration and strain-rate wave traverses the monolayer. When the wave passes to deeper cells, enhanced directionality is lost (B) theoretically, (C) and (D) experimentally), but the cells keep maintaining their elongated morphology. (F) Subjective single cells observations served as another indication for the validity of the experimental and theoretic results. Visualization of manual cell tracking (each cell marker with a different color) show that cells elongate to the direction of the wound edge followed by migration in a directional manner upon arrival of the waves. Time is in the format hh:mm. The corresponding video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/46351.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g005: A simplified model to test the hypothesis that strain rate triggers cellular directional response.(A) A qualitative description by a simple model of the relations between velocity, acceleration, strain rate, and directionality. Simulated particle velocity in the direction of the wound V+(t) (solid purple line), acceleration (dashed line), and linker attachment probability in the direction of the wound ρ(t) (solid yellow line). (B) Strain rate triggers a directional response (model calculation). Calculated ratio of the directional velocity parallel (V∥) to the directional velocity toward The wound (V+) as the acceleration wave propagates, for increasing sharpness of the wave (decreasing σ in Supporting Text S1), corresponding to a wave that is either sharper or with same σ but with larger overall peak acceleration leading to higher final velocity. Both give higher strain-rate and higher directionality according to our proposed relation of directionality on linker occupation (purple curve versus yellow curve as control). (C–D) Experimental results: scatter plot comparison of directionality: V+ vs. V∥. Each dot in the scatter plot represents an element (t,d) in the two Corresponding spatiotemporal maps. The results presented here were accumulated over all available experiments (N = 5 for HGF/SF treated cells, N = 6 for control cells). HGF/SF-treated DA3 cells migrate in an enhanced directional manner (D), compared to control cells (C), similarly to the corresponding theoretical purple and yellow plot in (B). (E) Morphology of single DA3 cells as function of time and distance from the wound. Average cell area (left panel) and eccentricity (elongation, right panel) as function of time. Cells stretch to become larger and more elongated as the acceleration and strain-rate wave traverses the monolayer. When the wave passes to deeper cells, enhanced directionality is lost (B) theoretically, (C) and (D) experimentally), but the cells keep maintaining their elongated morphology. (F) Subjective single cells observations served as another indication for the validity of the experimental and theoretic results. Visualization of manual cell tracking (each cell marker with a different color) show that cells elongate to the direction of the wound edge followed by migration in a directional manner upon arrival of the waves. Time is in the format hh:mm. The corresponding video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/46351.
Mentions: A simplified model was devised to test the hypothesis that strain rate (cellular stretching) leads to directional migration (See Supporting Text SI2 in Text S1). The cells were modeled as viscous elements which modify their shape in response to local stretching forces that are proportional to the strain-rate. The stretching forces associated with the acceleration wave can trigger a force-induced dissociation of cell-cell linkers in the direction of the stretch (i.e., towards the wound), thereby breaking the isotropy of the cell within the layer. This anisotropy is assumed to be trigger cell directionality: it can serve as a signal that recruits more actin-based motile machinery towards the wound compared to the orthogonal directions, creating a large velocity anisotropy ratio (Fig. 5). A simple linear relation between the stretch-induced linker anisotropy and the resulting velocity anisotropy ratio is assumed and gives good qualitative agreement with the experimental observations (Fig. 5).

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