Trends in Cell Biology
ReviewPlithotaxis and emergent dynamics in collective cellular migration
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)
- et al.
Cell migration during morphogenesis
Dev. Biol.
(2010) The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b
Curr. Biol.
(2007)Strength dependence of cadherin-mediated adhesions
Biophys. J.
(2010)- et al.
Organizing moving groups during morphogenesis
Curr. Opin. Cell Biol.
(2006) Mixed monolayers of natural and polymeric phospholipids: structural characterization by physical and enzymatic methods
Biochim. Biophys. Acta
(1990)The influence of cell mechanics, cell-cell interactions, and proliferation on epithelial packing
Curr. Biol.
(2007)Cell movement is guided by the rigidity of the substrate
Biophys. J.
(2000)Collective chemotaxis requires contact-dependent cell polarity
Dev. Cell
(2010)Movement directionality in collective migration of germ layer progenitors
Curr. Biol.
(2010)Velocity fields in a collectively migrating epithelium
Biophys. J.
(2010)
Moving and staying together without a leader
Phys. D
Positional information and the spatial pattern of cellular differentiation
J. Theor. Biol.
The bicoid protein determines position in the Drosophila embryo in a concentration-dependent manner
Cell
Dpp gradient formation in the Drosophila wing imaginal disc
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.
Cited by (195)
Collective migration of cells in geometric spaces: Intrinsic correlation length racing against extrinsic confinement size
2023, Journal of the Mechanics and Physics of SolidsMulticellular aligned bands disrupt global collective cell behavior
2023, Acta BiomaterialiaMechanical forces directing intestinal form and function
2022, Current BiologyActive chemo-mechanical feedbacks dictate the collective migration of cells on patterned surfaces
2022, Biophysical JournalCellular mechanics of wound formation in single cell layer under cyclic stretching
2022, Biophysical JournalPDGF-AA guides cell crosstalk between human dental pulp stem cells in vitro via the PDGFR-α/PI3K/Akt axis
2024, International Endodontic Journal