Plithotaxis and emergent dynamics in collective cellular migration

doi:10.1016/j.tcb.2011.06.006

Trends in Cell Biology

Volume 21, Issue 11, November 2011, Pages 638-646

https://doi.org/10.1016/j.tcb.2011.06.006 Get rights and content

For a monolayer sheet to migrate cohesively, it has long been suspected that each constituent cell must exert physical forces not only upon its extracellular matrix but also upon neighboring cells. The first comprehensive maps of these distinct force components reveal an unexpected physical picture. Rather than showing smooth and systematic variation within the monolayer, the distribution of physical forces is dominated by heterogeneity, both in space and in time, which emerges spontaneously, propagates over great distances, and cooperates over the span of many cell bodies. To explain the severe ruggedness of this force landscape and its role in collective cell guidance, the well known mechanisms of chemotaxis, durotaxis, haptotaxis are clearly insufficient. In a broad range of epithelial and endothelial cell sheets, collective cell migration is governed instead by a newly discovered emergent mechanism of innately collective cell guidance – plithotaxis.

Section snippets

Cellular motility within complex multicellular systems

In essential physiological functions including morphogenesis, wound healing, and tissue regeneration, the prevalent mode of cellular migration is collective. Collective cellular migration is also recognized as being a ubiquitous mechanism of invasion in cancers of epithelial origin. Indeed, virtually all living tissue is constructed and remodeled by collective cellular migration [1]. During morphogenesis, for example, the complex architecture of branched organs such as lung, kidney, pancreas,

If complexity is an essential feature, how much is enough?

Because of its importance to so many branches of biology, the question of collective cellular migration has been studied for a long time, at multiple levels, and in many different experimental model systems. For the particular questions at issue in this review, the intercellular forces that arise when only two or three cells interact in vitro 10, 11, 12 are of substantial interest even though such systems are not sufficiently complex to demonstrate the emergent phenomena described below. Of

The hidden hand

Collective cellular migration in a wide range of circumstances tends to be regulated by the same extrinsic cues that guide single cells in isolation, but these cues ordinarily act on but a small subset of cells that in turn guide naïve followers 1, 20. How does this subset within the motile group guide its global motion? The notion of a relay of guidance molecules is well studied, and it has it been suggested that the direct transmission of physical forces from cell–to–cell can be transduced

Making traction forces visible

The first direct measurements of traction forces exerted beneath an advancing cell sheet were obtained using micropillar assays [34], and, more recently, using traction microscopy [17]. With either approach, experiments demonstrate clearly that cells at the leading edge do indeed pull on their substrate in a direction consistent with pulling forward cells in the ranks behind, thus ruling out the notion that the leading monolayer edge is pushed forward by a compressive stress. Nonetheless, these

Dynamic heterogeneity: the median is not the message

With each cell of the continuous monolayer sheet being attached tightly to its substrate by adhesion molecules, being attached tightly to each neighboring cell by junctional proteins [36], and advancing systematically forward toward the leading edge, we had anticipated that the underlying pattern of traction forces that drives these motions would be comparably smooth, stable, and systematic, allowing, of course, for some modest degree of random biological noise. Observations show precisely the

Making intercellular forces visible

For any given cell within a monolayer, defining comprehensively the forces at work requires knowledge not only of the traction force exerted by that cell upon its substrate, but also the forces exerted at its boundaries with adjacent neighbors at cell–cell junctions (Figure 2). Measurement of these forces at cell–cell boundaries, as well as stresses borne within the cell body, is now accessible. Monolayer stress microscopy (MSM) starts with the traction forces at the cell-substrate interface of

A rugged stress landscape emerges from cooperative stress pile-up

Like maps of traction forces beneath epithelial or endothelial cell sheets, maps of inter- and intra-cellular stresses also reveal a physical picture that is dominated by dynamic heterogeneity. However, because the intercellular stress is essentially a spatial integral, or accumulation, of the traction forces (Figure 2), the length scale of its fluctuations is longer, and the time scale of its fluctuations is slower [18]. Even though structure is relatively homogeneous, mechanical stresses

Collective cell guidance

For the single cell in isolation to undergo directed migration, it must follow chemical or physical gradients. As a central part of the immune response, for example, the crawling neutrophil will follow the gradient of signals released by target pathogens or damaged cells (chemotaxis) [39]. Similarly, a cell that encounters a gradient in adhesion will tend to crawl up the adhesion gradient (haptotaxis), and a cell that encounters a gradient in substrate stiffness will tend to crawl up the

Plithotaxis

How are we to explain the motion of the individual cell navigating within the stormy monolayer? A mechanism was recently described by which collective cell guidance is mediated by the direct transmission of physical forces across cell–cell junctions [18]. From a map of the complete stress field within and between cells comprising the monolayer, the direction in which normal stresses (i.e. perpendicular to a surface) are maximal and minimal, respectively, can be determined. In engineering

Plithotaxis, crowding, and soft glasses

Anomalous behaviors of the kinds described above, taken together, are strongly reminiscent of what physicists call non-equilibrium matter [43], the paradigm of which is the special class of materials called soft glasses 43, 44. Glassy behavior is virtually ubiquitous in nature, subsuming molecular and polymeric liquids, granular media like sand and powders, colloidal suspensions, foams and pastes, plastics, metallic alloys, and even the cytoskeleton of the living cell 45, 46, 47, 48. Soft

Positional sensing

We now return to a central question in development and regeneration, namely, how are patterns of growth and differentiation specified? More specifically, within a homogeneous tissue, how does a cell know its location to differentiate into a specific cell type? Or within a growing tissue, how does a cell know when it must stop dividing? The prevalent answer to this question is that there must exist some form of positional sensing together with long-range feedback, such as a chemical gradient,

Concluding remarks

The existence of a relationship between physical forces and cellular motions for the monolayer in vitro is of course only a starting point for a more comprehensive understanding of collective cell migration in more complex systems. Future investigations need to address the extent to which the main behaviors found to date might scale up to tissues in vivo, which comprise greater phenotypic diversity and architectural complexity. Based upon existing data there is no reason to rule these behaviors

Acknowledgements

We are grateful to Dhananjay Tambe and James P. Butler for their comments, and to Thomas E Angelini and Xavier Serra-Picamal for artwork contribution. This research was supported by the Spanish Ministry for Science and Innovation (BFU2009-07595), the European Research Council (Grant Agreement 242993), and the National Institutes of Health (R01HL102373, R01HL107561).

Glossary

Stress: force per unit area.
Normal stress: local stress exerted normal to a defined surface.
Shear stress: local stress exerted tangent to a defined surface.
Traction force: the local stress exerted by a cell upon its substrate.
Principal stresses: in any continuum, the local stress field can be decomposed into a maximal and minimal principal stress, each acting along a corresponding principal orientation.
Principal orientations: orientations that are mutually perpendicular and define the directions along

References (70)

A. Aman et al.
Cell migration during morphogenesis
Dev. Biol.
(2010)
G. Valentin
The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b
Curr. Biol.
(2007)
B. Ladoux
Strength dependence of cadherin-mediated adhesions
Biophys. J.
(2010)
V. Lecaudey et al.
Organizing moving groups during morphogenesis
Curr. Opin. Cell Biol.
(2006)
D.W. Grainger
Mixed monolayers of natural and polymeric phospholipids: structural characterization by physical and enzymatic methods
Biochim. Biophys. Acta
(1990)
R. Farhadifar
The influence of cell mechanics, cell-cell interactions, and proliferation on epithelial packing
Curr. Biol.
(2007)
C.M. Lo
Cell movement is guided by the rigidity of the substrate
Biophys. J.
(2000)
E. Theveneau
Collective chemotaxis requires contact-dependent cell polarity
Dev. Cell
(2010)
Y. Arboleda-Estudillo
Movement directionality in collective migration of germ layer progenitors
Curr. Biol.
(2010)
L. Petitjean
Velocity fields in a collectively migrating epithelium
Biophys. J.
(2010)

G. Grégoire

Moving and staying together without a leader

Phys. D

(2003)

L. Wolpert

Positional information and the spatial pattern of cellular differentiation

J. Theor. Biol.

(1969)

W. Driever et al.

The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner

Cell

(1988)

A.A. Teleman et al.

Dpp gradient formation in the Drosophila wing imaginal disc

Cell

(2000)

P. Friedl et al.

Collective cell migration in morphogenesis, regeneration and cancer

Nat. Rev. Mol. Cell Biol.

(2009)

C.J. Weijer

Collective cell migration in development

J. Cell Sci.

(2009)

A. Bianco

Two distinct modes of guidance signalling during collective migration of border cells

Nature

(2007)

T.J. Shaw et al.

Wound repair at a glance

J. Cell Sci.

(2009)

S. Giampieri

Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility

Nat. Cell Biol.

(2009)

P. Friedl

Collective cell migration in morphogenesis and cancer

Int. J. Dev. Biol.

(2004)

K. Nabeshima

Cohort migration of carcinoma cells: differentiated colorectal carcinoma cells move as coherent cell clusters or sheets

Histol. Histopathol.

(1999)

Z. Liu

Mechanical tugging force regulates the size of cell-cell junctions

Proc. Natl. Acad. Sci. U.S.A.

(2010)

V. Maruthamuthu

Cell-ECM traction force modulates endogenous tension at cell-cell contacts

Proc. Natl. Acad. Sci. U.S.A.

(2011)

P. Vitorino et al.

Modular control of endothelial sheet migration

Genes Dev.

(2008)

K.J. Simpson

Identification of genes that regulate epithelial cell migration using an siRNA screening approach

Nat. Cell Biol.

(2008)

D.L. Nikolic

Role of boundary conditions in an experimental model of epithelial wound healing

Am. J. Physiol. Cell Physiol.

(2006)

M. Poujade

Collective migration of an epithelial monolayer in response to a model wound

Proc. Natl. Acad. Sci. U.S.A.

(2007)

X. Trepat

Physical forces during collective cell migration

Nat. Phys.

(2009)

D.T. Tambe

Collective cell guidance by cooperative intercellular forces

Nat. Mater.

(2011)

E. Fong

Boundary crossing in epithelial wound healing

Proc. Natl. Acad. Sci. U.S.A.

(2010)

S.J. Holmes

The behavior of the epidermis of amphibians when cultivated outside the body

J. Exp. Zool.

(1914)

R.B. Vaughan et al.

Movements of epithelial cell sheets in vitro

J. Cell Sci.

(1966)

T. Omelchenko

Rho-dependent formation of epithelial “leader” cells during wound healing

Proc. Natl. Acad. Sci. U.S.A.

(2003)

R. Farooqui et al.

Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement

J. Cell Sci.

(2005)

M. Bindschadler et al.

Sheet migration by wounded monolayers as an emergent property of single-cell dynamics

J. Cell Sci.

(2007)

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Many experiments showed that cell groups can exhibit various impressive motion modes (e.g., global rotation and local swirling) in different-sized geometrical spaces, with the underlying mechanisms still unclear. However, recent experiments showed that different types of cells perform distinct motion modes (i.e., global rotation and coherent oscillation) in the same constraint conditions, which brings further puzzles on the movements of collective cells. Here, by comprehensively considering the social interactions between adjacent cells and internal mechanical processes of the cell itself, we propose an active vertex model to bring physical insights into collective cell migration in geometrical constraints. Using this model, we can reproduce all reported motion modes of cells in circular constraints observed in existing experiments. Specifically, as the confinement size decreases, local swirling and global rotation modes successively appear in cell groups with finite correlation length, while eccentric rotation and coherent oscillation modes successively emerge in cell groups with scale-free correlations. We demonstrate that these distinct modes are subtly coded by the intrinsic correlation length of cell groups and the extrinsic confinement size. Unexpectedly, we discover that, in small-size confinements, cell groups with scale-free correlations can spontaneously transition from eccentric rotation into coherent oscillation modes, because the strong social interactions reconcile the movements of all cells. In addition, we propose a velocity indicator that can directly distinguish migration modes emerging in small-scale confinements. These findings are in broad agreement with many experiments, and shed light on the spatiotemporal dynamics of active matter.
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Mechanical stress patterns emerging from collective cell behavior have been shown to play critical roles in morphogenesis, tissue repair, and cancer metastasis. In our previous work, we constrained valvular interstitial cell (VIC) monolayers on circular protein islands to study emergent behavior in a controlled manner and demonstrated that the general patterns of cell alignment, size, and apoptosis correlate with predicted mechanical stress fields if radially increasing stiffness or contractility are used in the computational models. However, these radially symmetric models did not predict the existence of local regions of dense aligned cells observed in seemingly random locations of individual aggregates. The goal of this study is to determine how the heterogeneities in cell behavior emerge over time and diverge from the predicted collective cell behavior. Cell-cell interactions in circular multicellular aggregates of VICs were studied with time-lapse imaging ranging from hours to days, and migration, proliferation, and traction stresses were measured. Our results indicate that elongated cells create strong local alignment within preconfluent cell populations on the microcontact printed protein islands. These cells influence the alignment of additional cells to create dense, locally aligned bands of cells which disrupt the predicted global behavior. Cells are highly elongated at the endpoints of the bands yet have decreased spread area in the middle and reduced mobility. Although traction stresses at the endpoints of bands are enhanced, even to the point of detaching aggregates from the culture surface, the cells in dense bands exhibit reduced proliferation, less nuclear YAP, and increased apoptotic rates indicating a low stress environment. These findings suggest that strong local cell-cell interactions between primary fibroblastic cells can disrupt the global collective cellular behavior leading to substantial heterogeneity of cell behaviors in constrained monolayers. This local emergent behavior within aggregated fibroblasts may play an important role in development and disease of connective tissues.
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Trends in Cell Biology

ReviewPlithotaxis and emergent dynamics in collective cellular migration

Section snippets

Cellular motility within complex multicellular systems

If complexity is an essential feature, how much is enough?

The hidden hand

Making traction forces visible

Dynamic heterogeneity: the median is not the message

Making intercellular forces visible

A rugged stress landscape emerges from cooperative stress pile-up

Collective cell guidance

Plithotaxis

Plithotaxis, crowding, and soft glasses

Positional sensing

Concluding remarks

Acknowledgements

Glossary

Dev. Biol.

Curr. Biol.

Biophys. J.

Curr. Opin. Cell Biol.

Biochim. Biophys. Acta

Curr. Biol.

Biophys. J.

Dev. Cell

Curr. Biol.

Biophys. J.

Phys. D

J. Theor. Biol.

Cell

Cell

Collective cell migration in morphogenesis, regeneration and cancer

Nat. Rev. Mol. Cell Biol.

Collective cell migration in development

J. Cell Sci.

Two distinct modes of guidance signalling during collective migration of border cells

Nature

Wound repair at a glance

J. Cell Sci.

Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility

Nat. Cell Biol.

Collective cell migration in morphogenesis and cancer

Int. J. Dev. Biol.

Cohort migration of carcinoma cells: differentiated colorectal carcinoma cells move as coherent cell clusters or sheets

Histol. Histopathol.

Mechanical tugging force regulates the size of cell-cell junctions

Proc. Natl. Acad. Sci. U.S.A.

Cell-ECM traction force modulates endogenous tension at cell-cell contacts

Proc. Natl. Acad. Sci. U.S.A.

Modular control of endothelial sheet migration

Genes Dev.

Identification of genes that regulate epithelial cell migration using an siRNA screening approach

Nat. Cell Biol.

Role of boundary conditions in an experimental model of epithelial wound healing

Am. J. Physiol. Cell Physiol.

Collective migration of an epithelial monolayer in response to a model wound

Proc. Natl. Acad. Sci. U.S.A.

Physical forces during collective cell migration

Nat. Phys.

Collective cell guidance by cooperative intercellular forces

Nat. Mater.

Boundary crossing in epithelial wound healing

Proc. Natl. Acad. Sci. U.S.A.

The behavior of the epidermis of amphibians when cultivated outside the body

J. Exp. Zool.

Movements of epithelial cell sheets in vitro

J. Cell Sci.

Rho-dependent formation of epithelial “leader” cells during wound healing

Proc. Natl. Acad. Sci. U.S.A.

Multiple rows of cells behind an epithelial wound edge extend cryptic lamellipodia to collectively drive cell-sheet movement

J. Cell Sci.

Sheet migration by wounded monolayers as an emergent property of single-cell dynamics

J. Cell Sci.

Review
Plithotaxis and emergent dynamics in collective cellular migration