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Dynamic tensile forces drive collective cell migration through three-dimensional extracellular matrices.

Gjorevski N, Piotrowski AS, Varner VD, Nelson CM - Sci Rep (2015)

Bottom Line: Moreover, cell movements are highly correlated and in phase with ECM deformations.Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate through the ECM.These results suggest biophysical forces are critical for 3D collective migration.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical &Biological Engineering, Princeton University, Princeton, NJ 08544, USA.

ABSTRACT
Collective cell migration drives tissue remodeling during development, wound repair, and metastatic invasion. The physical mechanisms by which cells move cohesively through dense three-dimensional (3D) extracellular matrix (ECM) remain incompletely understood. Here, we show directly that migration of multicellular cohorts through collagenous matrices occurs via a dynamic pulling mechanism, the nature of which had only been inferred previously in 3D. Tensile forces increase at the invasive front of cohorts, serving a physical, propelling role as well as a regulatory one by conditioning the cells and matrix for further extension. These forces elicit mechanosensitive signaling within the leading edge and align the ECM, creating microtracks conducive to further migration. Moreover, cell movements are highly correlated and in phase with ECM deformations. Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate through the ECM. These results suggest biophysical forces are critical for 3D collective migration.

No MeSH data available.


Collectively migrating cohorts exhibit dynamic changes in shape, which are in phase and correlated with surrounding matrix deformations.(a) Confocal fluorescence image of a collectively migrating cohort after 40 hours of live imaging with bead displacements superimposed (red). Image is representative of 4 independent replicates. Within a single experiment, four tissues were monitored. Contours of the migrating cohort in (a) from (b) 0 to 20 hours and from (c) 20 to 40 hours; darker colors represent later time points. (d) Plot of normalized cohort length (blue, dashed line) and projected area (red, solid line) for the cohort in (a). (e) Plot of normalized cohort length (blue, dashed line) and displacements (various colors, solid lines) of beads near (<50 μm) the migrating cohort in (a). Displacements are representative of 18 tracks analyzed. Also included is the displacement (black, dotted line) of one bead located far (>50 μm) from the migrating cohort. (f) Sample cross correlation plot comparing variations in cohort length to the displacement of a bead located near the migrating cohort (sample cross covariance). Plot is representative of 18 displacement tracks analyzed. (g) Cross correlation coefficients comparing temporal change in cohort length to the displacement trajectories of fluorescent beads near the cohort and far from the cohort for two separate representative samples. Mean of four replicates is shown. Beads near cohort 1: n = 7; beads far from cohort 1: n = 11; beads near cohort 2: n = 7; beads far from cohort 2: n = 7. ***P < 0.001, Student’s t-test. Scale bar, 50 μm.
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f2: Collectively migrating cohorts exhibit dynamic changes in shape, which are in phase and correlated with surrounding matrix deformations.(a) Confocal fluorescence image of a collectively migrating cohort after 40 hours of live imaging with bead displacements superimposed (red). Image is representative of 4 independent replicates. Within a single experiment, four tissues were monitored. Contours of the migrating cohort in (a) from (b) 0 to 20 hours and from (c) 20 to 40 hours; darker colors represent later time points. (d) Plot of normalized cohort length (blue, dashed line) and projected area (red, solid line) for the cohort in (a). (e) Plot of normalized cohort length (blue, dashed line) and displacements (various colors, solid lines) of beads near (<50 μm) the migrating cohort in (a). Displacements are representative of 18 tracks analyzed. Also included is the displacement (black, dotted line) of one bead located far (>50 μm) from the migrating cohort. (f) Sample cross correlation plot comparing variations in cohort length to the displacement of a bead located near the migrating cohort (sample cross covariance). Plot is representative of 18 displacement tracks analyzed. (g) Cross correlation coefficients comparing temporal change in cohort length to the displacement trajectories of fluorescent beads near the cohort and far from the cohort for two separate representative samples. Mean of four replicates is shown. Beads near cohort 1: n = 7; beads far from cohort 1: n = 11; beads near cohort 2: n = 7; beads far from cohort 2: n = 7. ***P < 0.001, Student’s t-test. Scale bar, 50 μm.

Mentions: Live imaging revealed the dynamics of collective migration and the interactions between the cells and their surrounding ECM (Fig. 2a). Collectively migrating cohorts exhibited dynamic changes in shape during migration (Fig. 2b,c). The projected area of the cohorts increased relatively linearly in time, while their lengths fluctuated (Fig. 2d). Comparing bead displacements to changes in cohort length revealed that beads adjacent to the extending collective moved coordinately and in phase with the cohort (Fig. 2e–g). Beads far from the migrating cohort (>50 μm) showed little displacement, and their movements did not correlate with that of the cohort (Fig. 2g). We also noted that cohorts continuously exert a tensile force on the ECM during extension, holding the ECM taut during migration (Supplemental Movie 2).


Dynamic tensile forces drive collective cell migration through three-dimensional extracellular matrices.

Gjorevski N, Piotrowski AS, Varner VD, Nelson CM - Sci Rep (2015)

Collectively migrating cohorts exhibit dynamic changes in shape, which are in phase and correlated with surrounding matrix deformations.(a) Confocal fluorescence image of a collectively migrating cohort after 40 hours of live imaging with bead displacements superimposed (red). Image is representative of 4 independent replicates. Within a single experiment, four tissues were monitored. Contours of the migrating cohort in (a) from (b) 0 to 20 hours and from (c) 20 to 40 hours; darker colors represent later time points. (d) Plot of normalized cohort length (blue, dashed line) and projected area (red, solid line) for the cohort in (a). (e) Plot of normalized cohort length (blue, dashed line) and displacements (various colors, solid lines) of beads near (<50 μm) the migrating cohort in (a). Displacements are representative of 18 tracks analyzed. Also included is the displacement (black, dotted line) of one bead located far (>50 μm) from the migrating cohort. (f) Sample cross correlation plot comparing variations in cohort length to the displacement of a bead located near the migrating cohort (sample cross covariance). Plot is representative of 18 displacement tracks analyzed. (g) Cross correlation coefficients comparing temporal change in cohort length to the displacement trajectories of fluorescent beads near the cohort and far from the cohort for two separate representative samples. Mean of four replicates is shown. Beads near cohort 1: n = 7; beads far from cohort 1: n = 11; beads near cohort 2: n = 7; beads far from cohort 2: n = 7. ***P < 0.001, Student’s t-test. Scale bar, 50 μm.
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f2: Collectively migrating cohorts exhibit dynamic changes in shape, which are in phase and correlated with surrounding matrix deformations.(a) Confocal fluorescence image of a collectively migrating cohort after 40 hours of live imaging with bead displacements superimposed (red). Image is representative of 4 independent replicates. Within a single experiment, four tissues were monitored. Contours of the migrating cohort in (a) from (b) 0 to 20 hours and from (c) 20 to 40 hours; darker colors represent later time points. (d) Plot of normalized cohort length (blue, dashed line) and projected area (red, solid line) for the cohort in (a). (e) Plot of normalized cohort length (blue, dashed line) and displacements (various colors, solid lines) of beads near (<50 μm) the migrating cohort in (a). Displacements are representative of 18 tracks analyzed. Also included is the displacement (black, dotted line) of one bead located far (>50 μm) from the migrating cohort. (f) Sample cross correlation plot comparing variations in cohort length to the displacement of a bead located near the migrating cohort (sample cross covariance). Plot is representative of 18 displacement tracks analyzed. (g) Cross correlation coefficients comparing temporal change in cohort length to the displacement trajectories of fluorescent beads near the cohort and far from the cohort for two separate representative samples. Mean of four replicates is shown. Beads near cohort 1: n = 7; beads far from cohort 1: n = 11; beads near cohort 2: n = 7; beads far from cohort 2: n = 7. ***P < 0.001, Student’s t-test. Scale bar, 50 μm.
Mentions: Live imaging revealed the dynamics of collective migration and the interactions between the cells and their surrounding ECM (Fig. 2a). Collectively migrating cohorts exhibited dynamic changes in shape during migration (Fig. 2b,c). The projected area of the cohorts increased relatively linearly in time, while their lengths fluctuated (Fig. 2d). Comparing bead displacements to changes in cohort length revealed that beads adjacent to the extending collective moved coordinately and in phase with the cohort (Fig. 2e–g). Beads far from the migrating cohort (>50 μm) showed little displacement, and their movements did not correlate with that of the cohort (Fig. 2g). We also noted that cohorts continuously exert a tensile force on the ECM during extension, holding the ECM taut during migration (Supplemental Movie 2).

Bottom Line: Moreover, cell movements are highly correlated and in phase with ECM deformations.Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate through the ECM.These results suggest biophysical forces are critical for 3D collective migration.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical &Biological Engineering, Princeton University, Princeton, NJ 08544, USA.

ABSTRACT
Collective cell migration drives tissue remodeling during development, wound repair, and metastatic invasion. The physical mechanisms by which cells move cohesively through dense three-dimensional (3D) extracellular matrix (ECM) remain incompletely understood. Here, we show directly that migration of multicellular cohorts through collagenous matrices occurs via a dynamic pulling mechanism, the nature of which had only been inferred previously in 3D. Tensile forces increase at the invasive front of cohorts, serving a physical, propelling role as well as a regulatory one by conditioning the cells and matrix for further extension. These forces elicit mechanosensitive signaling within the leading edge and align the ECM, creating microtracks conducive to further migration. Moreover, cell movements are highly correlated and in phase with ECM deformations. Migrating cohorts use spatially localized, long-range forces and consequent matrix alignment to navigate through the ECM. These results suggest biophysical forces are critical for 3D collective migration.

No MeSH data available.