Limits...
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.

Show MeSH

Related in: MedlinePlus

Backward propagating wave and its effect on the physical properties measured.(A) Backward propagating waves were observed for various cellular physical properties during in vitro wound healing assays. Regardless of the property measured, a spatial pulse-like profile was observed. For example, for a specific time point t (blue) cells near the wound edge do not accelerate, the pulse is maximized for deeper cells and then decreases for cell located farther from the wound edge. With time (t+1, red), the pulse's maximum is propagating farther back from the front. Not only that the pulse response maximum is located farther in response to the wound edge (dt<dt+Δt), but also the wave propagates backward even faster than the actual speed of the wound edge; vedgeΔt+dt<dt+Δt. Note that throughout the text, the waves were recorded in relation to the (advancing) leading edge. (B–E) The physical traits measured and their alternation in response to the peak in the backward propagating wave. t, t+Δt correspond to time points before and after the pulse's peek approaches a cell (a pulse profile is sketched below for illustration). (B) Acceleration, local temporal derivative of speed. Upon acceleration wave, the cells migrate faster. (C) Strain rate, local spatial derivative of speed. This is an implicit measure for cell stretching/deformation. Upon strain rate wave, the cells elongate. (D) Directionality, ratio between the magnitude of the local velocity component toward- and parallel- to the wound edge. Upon directionality wave, the cells migrate with enhanced directionality. (E) Coordination, the fraction of cells that migrate as clusters with coordinated trajectories. Upon coordination wave, more adjacent cells coordinate their trajectories.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4109844&req=5

pcbi-1003747-g001: Backward propagating wave and its effect on the physical properties measured.(A) Backward propagating waves were observed for various cellular physical properties during in vitro wound healing assays. Regardless of the property measured, a spatial pulse-like profile was observed. For example, for a specific time point t (blue) cells near the wound edge do not accelerate, the pulse is maximized for deeper cells and then decreases for cell located farther from the wound edge. With time (t+1, red), the pulse's maximum is propagating farther back from the front. Not only that the pulse response maximum is located farther in response to the wound edge (dt<dt+Δt), but also the wave propagates backward even faster than the actual speed of the wound edge; vedgeΔt+dt<dt+Δt. Note that throughout the text, the waves were recorded in relation to the (advancing) leading edge. (B–E) The physical traits measured and their alternation in response to the peak in the backward propagating wave. t, t+Δt correspond to time points before and after the pulse's peek approaches a cell (a pulse profile is sketched below for illustration). (B) Acceleration, local temporal derivative of speed. Upon acceleration wave, the cells migrate faster. (C) Strain rate, local spatial derivative of speed. This is an implicit measure for cell stretching/deformation. Upon strain rate wave, the cells elongate. (D) Directionality, ratio between the magnitude of the local velocity component toward- and parallel- to the wound edge. Upon directionality wave, the cells migrate with enhanced directionality. (E) Coordination, the fraction of cells that migrate as clusters with coordinated trajectories. Upon coordination wave, more adjacent cells coordinate their trajectories.

Mentions: Here we reveal that collective cell migration is more intricate than was previously reported. We applied specially-designed analytical techniques to investigate the spatiotemporal dynamics of acceleration, cellular stretching (strain rate), directionality and coordination, and their associations and temporal order. We found that these quantities can exhibit wave-like phenomena, which move backward in respect to the monolayer's moving direction - away from the wound edge. The wave's profile is similar to a pulse: low acceleration is observed for the cells that are close to the edge, the acceleration increases for the cells that are behind them, and decreases again for cells that are farther away. The location of the maximal acceleration moves backward, i.e., in a direction opposite to the motion of the monolayer itself. We refer to this phenomenon as backward propagating wave, and it is sketched in Fig. 1A.


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)

Backward propagating wave and its effect on the physical properties measured.(A) Backward propagating waves were observed for various cellular physical properties during in vitro wound healing assays. Regardless of the property measured, a spatial pulse-like profile was observed. For example, for a specific time point t (blue) cells near the wound edge do not accelerate, the pulse is maximized for deeper cells and then decreases for cell located farther from the wound edge. With time (t+1, red), the pulse's maximum is propagating farther back from the front. Not only that the pulse response maximum is located farther in response to the wound edge (dt<dt+Δt), but also the wave propagates backward even faster than the actual speed of the wound edge; vedgeΔt+dt<dt+Δt. Note that throughout the text, the waves were recorded in relation to the (advancing) leading edge. (B–E) The physical traits measured and their alternation in response to the peak in the backward propagating wave. t, t+Δt correspond to time points before and after the pulse's peek approaches a cell (a pulse profile is sketched below for illustration). (B) Acceleration, local temporal derivative of speed. Upon acceleration wave, the cells migrate faster. (C) Strain rate, local spatial derivative of speed. This is an implicit measure for cell stretching/deformation. Upon strain rate wave, the cells elongate. (D) Directionality, ratio between the magnitude of the local velocity component toward- and parallel- to the wound edge. Upon directionality wave, the cells migrate with enhanced directionality. (E) Coordination, the fraction of cells that migrate as clusters with coordinated trajectories. Upon coordination wave, more adjacent cells coordinate their trajectories.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g001: Backward propagating wave and its effect on the physical properties measured.(A) Backward propagating waves were observed for various cellular physical properties during in vitro wound healing assays. Regardless of the property measured, a spatial pulse-like profile was observed. For example, for a specific time point t (blue) cells near the wound edge do not accelerate, the pulse is maximized for deeper cells and then decreases for cell located farther from the wound edge. With time (t+1, red), the pulse's maximum is propagating farther back from the front. Not only that the pulse response maximum is located farther in response to the wound edge (dt<dt+Δt), but also the wave propagates backward even faster than the actual speed of the wound edge; vedgeΔt+dt<dt+Δt. Note that throughout the text, the waves were recorded in relation to the (advancing) leading edge. (B–E) The physical traits measured and their alternation in response to the peak in the backward propagating wave. t, t+Δt correspond to time points before and after the pulse's peek approaches a cell (a pulse profile is sketched below for illustration). (B) Acceleration, local temporal derivative of speed. Upon acceleration wave, the cells migrate faster. (C) Strain rate, local spatial derivative of speed. This is an implicit measure for cell stretching/deformation. Upon strain rate wave, the cells elongate. (D) Directionality, ratio between the magnitude of the local velocity component toward- and parallel- to the wound edge. Upon directionality wave, the cells migrate with enhanced directionality. (E) Coordination, the fraction of cells that migrate as clusters with coordinated trajectories. Upon coordination wave, more adjacent cells coordinate their trajectories.
Mentions: Here we reveal that collective cell migration is more intricate than was previously reported. We applied specially-designed analytical techniques to investigate the spatiotemporal dynamics of acceleration, cellular stretching (strain rate), directionality and coordination, and their associations and temporal order. We found that these quantities can exhibit wave-like phenomena, which move backward in respect to the monolayer's moving direction - away from the wound edge. The wave's profile is similar to a pulse: low acceleration is observed for the cells that are close to the edge, the acceleration increases for the cells that are behind them, and decreases again for cells that are farther away. The location of the maximal acceleration moves backward, i.e., in a direction opposite to the motion of the monolayer itself. We refer to this phenomenon as backward propagating wave, and it is sketched in Fig. 1A.

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