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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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Overview of the wound healing spatiotemporal dynamics.(A) Snapshots from a wound healing assay of DA3 cells treated with HGF/SF. The color bands are used to visualize the locations of elevated cellular acceleration and stretching (green), directionality (purple) and their overlay (cyan), and were calculated from the experimental data by segmenting the corresponding kymographs. d1<d2<d3 represent the location of currently accelerating cells demonstrating the wave's backward propagation. The full video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/45355. (B) Analysis of a wound healing assay of DA3 cells treated with HGF/SF. Strain rate, directionality and coordination were recorded as function from the wound edge for 3 time intervals: 0–100, 100–200 and 200–300 minutes. Note that strain rate (green) precedes directionality (blue) and coordination (red). (C) The general schema: acceleration and stretching (morphological deformation) followed by increased directionality and enhanced coordination. (D) Single vs. Group HGF/SF-Induced migration. Sketch of a different phenomenon observed in single vs. collective migration as a response to HGF/SF. Upon treatment, non-confluent cells accelerate, spread and scatter, whereas confluent monolayers accelerate, deform to a more elongated morphology and amplify intercellular coordination. This transition from low- to high-coordination in the single-cell and collective settings is of great interest for future studies.
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pcbi-1003747-g008: Overview of the wound healing spatiotemporal dynamics.(A) Snapshots from a wound healing assay of DA3 cells treated with HGF/SF. The color bands are used to visualize the locations of elevated cellular acceleration and stretching (green), directionality (purple) and their overlay (cyan), and were calculated from the experimental data by segmenting the corresponding kymographs. d1<d2<d3 represent the location of currently accelerating cells demonstrating the wave's backward propagation. The full video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/45355. (B) Analysis of a wound healing assay of DA3 cells treated with HGF/SF. Strain rate, directionality and coordination were recorded as function from the wound edge for 3 time intervals: 0–100, 100–200 and 200–300 minutes. Note that strain rate (green) precedes directionality (blue) and coordination (red). (C) The general schema: acceleration and stretching (morphological deformation) followed by increased directionality and enhanced coordination. (D) Single vs. Group HGF/SF-Induced migration. Sketch of a different phenomenon observed in single vs. collective migration as a response to HGF/SF. Upon treatment, non-confluent cells accelerate, spread and scatter, whereas confluent monolayers accelerate, deform to a more elongated morphology and amplify intercellular coordination. This transition from low- to high-coordination in the single-cell and collective settings is of great interest for future studies.

Mentions: It is well established that in response to HGF/SF, epithelial monolayers become sparser, maintain higher motility [29], and weaken cell–cell contacts [25]. Nevertheless, higher intercellular coordination was found here as response to HGF/SF (Fig. 8D). This observation may imply an alternative channel of mechanical intercellular communication [25], [45]. For example, a mechanism that is based on emerged collective sensing from individuals modulating their speed in response to local cues through social interaction with their peers [46] may explain our findings. We speculate that the wave of directionality has an important role in this phenomenon, and that increased motility coupled with a general directional cue introduced by the free edge is more prominent than the known density-motility-coordination intrinsic relations, thus leading to increased coordination.


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)

Overview of the wound healing spatiotemporal dynamics.(A) Snapshots from a wound healing assay of DA3 cells treated with HGF/SF. The color bands are used to visualize the locations of elevated cellular acceleration and stretching (green), directionality (purple) and their overlay (cyan), and were calculated from the experimental data by segmenting the corresponding kymographs. d1<d2<d3 represent the location of currently accelerating cells demonstrating the wave's backward propagation. The full video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/45355. (B) Analysis of a wound healing assay of DA3 cells treated with HGF/SF. Strain rate, directionality and coordination were recorded as function from the wound edge for 3 time intervals: 0–100, 100–200 and 200–300 minutes. Note that strain rate (green) precedes directionality (blue) and coordination (red). (C) The general schema: acceleration and stretching (morphological deformation) followed by increased directionality and enhanced coordination. (D) Single vs. Group HGF/SF-Induced migration. Sketch of a different phenomenon observed in single vs. collective migration as a response to HGF/SF. Upon treatment, non-confluent cells accelerate, spread and scatter, whereas confluent monolayers accelerate, deform to a more elongated morphology and amplify intercellular coordination. This transition from low- to high-coordination in the single-cell and collective settings is of great interest for future studies.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003747-g008: Overview of the wound healing spatiotemporal dynamics.(A) Snapshots from a wound healing assay of DA3 cells treated with HGF/SF. The color bands are used to visualize the locations of elevated cellular acceleration and stretching (green), directionality (purple) and their overlay (cyan), and were calculated from the experimental data by segmenting the corresponding kymographs. d1<d2<d3 represent the location of currently accelerating cells demonstrating the wave's backward propagation. The full video is freely available at “The Cell: an Image Library”, http://www.cellimagelibrary.org/images/45355. (B) Analysis of a wound healing assay of DA3 cells treated with HGF/SF. Strain rate, directionality and coordination were recorded as function from the wound edge for 3 time intervals: 0–100, 100–200 and 200–300 minutes. Note that strain rate (green) precedes directionality (blue) and coordination (red). (C) The general schema: acceleration and stretching (morphological deformation) followed by increased directionality and enhanced coordination. (D) Single vs. Group HGF/SF-Induced migration. Sketch of a different phenomenon observed in single vs. collective migration as a response to HGF/SF. Upon treatment, non-confluent cells accelerate, spread and scatter, whereas confluent monolayers accelerate, deform to a more elongated morphology and amplify intercellular coordination. This transition from low- to high-coordination in the single-cell and collective settings is of great interest for future studies.
Mentions: It is well established that in response to HGF/SF, epithelial monolayers become sparser, maintain higher motility [29], and weaken cell–cell contacts [25]. Nevertheless, higher intercellular coordination was found here as response to HGF/SF (Fig. 8D). This observation may imply an alternative channel of mechanical intercellular communication [25], [45]. For example, a mechanism that is based on emerged collective sensing from individuals modulating their speed in response to local cues through social interaction with their peers [46] may explain our findings. We speculate that the wave of directionality has an important role in this phenomenon, and that increased motility coupled with a general directional cue introduced by the free edge is more prominent than the known density-motility-coordination intrinsic relations, thus leading to increased coordination.

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