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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.


Tensile forces remodel matrix at the leading edge of migrating cohorts.(a) Representative phase contrast image showing cells invading from a mammary epithelial cell cluster. (b) Confocal reflection image depicting the structure of the collagen matrix surrounding the tissue in (a). (c) Merged image of (a) and (b). High magnification images showing the structure of the collagen (d) far from the invading tissue in (a) and (f) adjacent to the invasive front of the tissue in (a). (e) Rose plot showing fibril angles far from the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (d). (g) Rose plot showing fibril angles adjacent to the invasive front of the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (f). Red line indicates the direction of collective invasion. All images are representative of three independent replicates. Scale bars, 50 μm (a–c), 25 μm (d,f).
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f4: Tensile forces remodel matrix at the leading edge of migrating cohorts.(a) Representative phase contrast image showing cells invading from a mammary epithelial cell cluster. (b) Confocal reflection image depicting the structure of the collagen matrix surrounding the tissue in (a). (c) Merged image of (a) and (b). High magnification images showing the structure of the collagen (d) far from the invading tissue in (a) and (f) adjacent to the invasive front of the tissue in (a). (e) Rose plot showing fibril angles far from the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (d). (g) Rose plot showing fibril angles adjacent to the invasive front of the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (f). Red line indicates the direction of collective invasion. All images are representative of three independent replicates. Scale bars, 50 μm (a–c), 25 μm (d,f).

Mentions: It has been proposed that during collective invasion through collagenous matrices, cells follow paths of least resistance created by proteolytic degradation and softening of the ECM36. To test for such a mechanism, we used confocal reflection microscopy (CRM) to visualize the structure of the matrix surrounding the invading cohorts (Fig. S3a). We observed no obvious proteolytic remodeling ahead of the leading edge (Fig. 4a-c; Fig. S3a–c). Instead, CRM revealed a different kind of matrix remodeling at these locations: collagen fibrils were compacted and aligned into parallel and highly directional tracks emanating from the invasive front and propagating over distances spanning ~100 μm from the tissue (Fig. 4c). Measuring the angles of collagen fibrils revealed that those far from the tissue (Fig. 4d) were distributed randomly (Fig. 4e), while those ahead of the migrating cohort (Fig. 4f) oriented preferentially in the direction of migration (Fig. 4g). Imaging the matrix around primary organoids similarly revealed that collagen was compacted into dense and directionally oriented fibrils from the leading edge of extending branches (Fig. S3e–g). Blocking cytoskeletal tension prevented collagen alignment ahead of the migrating cohorts (Fig. S3i), suggesting that alignment was mediated by migration-generated tensile forces.


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

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

Tensile forces remodel matrix at the leading edge of migrating cohorts.(a) Representative phase contrast image showing cells invading from a mammary epithelial cell cluster. (b) Confocal reflection image depicting the structure of the collagen matrix surrounding the tissue in (a). (c) Merged image of (a) and (b). High magnification images showing the structure of the collagen (d) far from the invading tissue in (a) and (f) adjacent to the invasive front of the tissue in (a). (e) Rose plot showing fibril angles far from the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (d). (g) Rose plot showing fibril angles adjacent to the invasive front of the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (f). Red line indicates the direction of collective invasion. All images are representative of three independent replicates. Scale bars, 50 μm (a–c), 25 μm (d,f).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499882&req=5

f4: Tensile forces remodel matrix at the leading edge of migrating cohorts.(a) Representative phase contrast image showing cells invading from a mammary epithelial cell cluster. (b) Confocal reflection image depicting the structure of the collagen matrix surrounding the tissue in (a). (c) Merged image of (a) and (b). High magnification images showing the structure of the collagen (d) far from the invading tissue in (a) and (f) adjacent to the invasive front of the tissue in (a). (e) Rose plot showing fibril angles far from the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (d). (g) Rose plot showing fibril angles adjacent to the invasive front of the tissue in (a). Histogram represents fiber angles computed at 900 image locations within (f). Red line indicates the direction of collective invasion. All images are representative of three independent replicates. Scale bars, 50 μm (a–c), 25 μm (d,f).
Mentions: It has been proposed that during collective invasion through collagenous matrices, cells follow paths of least resistance created by proteolytic degradation and softening of the ECM36. To test for such a mechanism, we used confocal reflection microscopy (CRM) to visualize the structure of the matrix surrounding the invading cohorts (Fig. S3a). We observed no obvious proteolytic remodeling ahead of the leading edge (Fig. 4a-c; Fig. S3a–c). Instead, CRM revealed a different kind of matrix remodeling at these locations: collagen fibrils were compacted and aligned into parallel and highly directional tracks emanating from the invasive front and propagating over distances spanning ~100 μm from the tissue (Fig. 4c). Measuring the angles of collagen fibrils revealed that those far from the tissue (Fig. 4d) were distributed randomly (Fig. 4e), while those ahead of the migrating cohort (Fig. 4f) oriented preferentially in the direction of migration (Fig. 4g). Imaging the matrix around primary organoids similarly revealed that collagen was compacted into dense and directionally oriented fibrils from the leading edge of extending branches (Fig. S3e–g). Blocking cytoskeletal tension prevented collagen alignment ahead of the migrating cohorts (Fig. S3i), suggesting that alignment was mediated by migration-generated tensile forces.

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.