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Collective cell migration has distinct directionality and speed dynamics.

ABSTRACT: When a constraint is removed, confluent cells migrate directionally into the available space. How the migration directionality and speed increase are initiated at the leading edge and propagate into neighboring cells are not well understood. Using a quantitative visualization technique-Particle Image Velocimetry (PIV)-we revealed that migration directionality and speed had strikingly different dynamics. Migration directionality increases as a wave propagating from the leading edge into the cell sheet, while the increase in cell migration speed is maintained only at the leading edge. The overall directionality steadily increases with time as cells migrate into the cell-free space, but migration speed remains largely the same. A particle-based compass (PBC) model suggests cellular interplay (which depends on cell-cell distance) and migration speed are sufficient to capture the dynamics of migration directionality revealed experimentally. Extracellular Ca2+ regulated both migration speed and directionality, but in a significantly different way, suggested by the correlation between directionality and speed only in some dynamic ranges. Our experimental and modeling results reveal distinct directionality and speed dynamics in collective migration, and these factors can be regulated by extracellular Ca2+ through cellular interplay. Quantitative visualization using PIV and our PBC model thus provide a powerful approach to dissect the mechanisms of collective cell migration.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5709186 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Collective cell migration has distinct directionality and speed dynamics.

Zhang Yan Y Xu Guoqing G Lee Rachel M RM Zhu Zijie Z Wu Jiandong J Liao Simon S Zhang Gong G Sun Yaohui Y Mogilner Alex A Losert Wolfgang W Pan Tingrui T Lin Francis F Xu Zhengping Z Zhao Min M

Cellular and molecular life sciences : CMLS 20170613 20

When a constraint is removed, confluent cells migrate directionally into the available space. How the migration directionality and speed increase are initiated at the leading edge and propagate into neighboring cells are not well understood. Using a quantitative visualization technique-Particle Image Velocimetry (PIV)-we revealed that migration directionality and speed had strikingly different dynamics. Migration directionality increases as a wave propagating from the leading edge into the cell ...[more]

PMID: 28612218

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Project description: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.

Project description:Collective cell migration is a common phenotype in epithelial cancers, which is associated with tumor cell metastasis and poor patient survival. However, the interplay between physiologically relevant pro-migratory stimuli and the underlying mechanical cell-cell interactions are poorly understood. We investigated the migratory behavior of different collectively migrating non-small cell lung cancer cell lines in response to motogenic growth factors (e.g. epidermal growth factor) or clinically relevant small compound inhibitors. Depending on the treatment, we observed distinct behaviors in a classical lateral migration assay involving traveling fronts, finger-shapes or the development of cellular bridges. Particle image velocimetry analysis revealed characteristic speed dynamics (evolution of the average speed of all cells in a frame) in all experiments exhibiting initial acceleration and subsequent deceleration of the cell populations. To better understand the mechanical properties of individual cells leading to the observed speed dynamics and the phenotypic differences we developed a mathematical model based on a Langevin approach. This model describes intercellular forces, random motility, and stimulation of active migration by mechanical interaction between cells. Simulations show that the model is able to reproduce the characteristic spatio-temporal speed distributions as well as most migratory phenotypes of the studied cell lines. A specific strength of the proposed model is that it identifies a small set of mechanical features necessary to explain all phenotypic and dynamical features of the migratory response of non-small cell lung cancer cells to chemical stimulation/inhibition. Furthermore, all processes included in the model can be associated with potential molecular components, and are therefore amenable to experimental validation. Thus, the presented mathematical model may help to predict which mechanical aspects involved in non-small cell lung cancer cell migration are affected by the respective therapeutic treatment.

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Collective cell migration has distinct directionality and speed dynamics.

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Collective cell migration has distinct directionality and speed dynamics.

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