Trends in Cell Biology
Volume 30, Issue 11, November 2020, Pages 852-868
Journal home page for Trends in Cell Biology

Review
All Roads Lead to Directional Cell Migration

https://doi.org/10.1016/j.tcb.2020.08.002Get rights and content

Highlights

  • Many different types of stimuli for directional migration have been identified within the overarching categories of chemical, mechanical, and electrical cues.

  • The in vitro data for many signals directing cell migration are convincing, but limited evidence exists in vivo.

  • Stimuli that direct cell migration can be spatially organised by nonmigrating cells as well as by the responsive migratory cells themselves in a highly dynamic fashion.

  • The mechanisms by which different types of stimuli are sensed and transduced is varied, but there may be a common subset of effectors that govern directional cell movement.

Directional cell migration normally relies on a variety of external signals, such as chemical, mechanical, or electrical, which instruct cells in which direction to move. Many of the major molecular and physical effects derived from these cues are now understood, leading to questions about whether directional cell migration is alike or distinct under these different signals, and how cells might be directed by multiple simultaneous cues, which would be expected in complex in vivo environments. In this review, we compare how different stimuli are spatially distributed, often as gradients, to direct cell movement and the mechanisms by which they steer cells. A comparison of the downstream effectors of directional cues suggests that different external signals regulate a common set of components: small GTPases and the actin cytoskeleton, which implies that the mechanisms downstream of different signals are likely to be closely related and underlies the idea that cell migration operates by a common set of physical principles, irrespective of the input.

Section snippets

Directional Cell Migration

Cell migration orchestrates key events in development, homeostasis, and disease [1]. Cells can move individually [2] or as collectives [3]. The direction in which cells move is rarely random; in most cases, migration occurs in a highly directional manner, whereby cells translocate from one specific location to another. For example, immune cells move towards sites of infection; bacteria migrate toward nutrient sources; radial glia cells, germ cells, and neural crest cells migrate long distances

Principles of Cell Migration

The principal concepts underlying adherent cell migration are well understood (Figure 2) [4]. For a cell to migrate directionally it needs to become polarised, meaning the front becomes distinct from the back of the cell (Figure 2A,B). Fundamental to this breaking of symmetry is actin polymerisation at the leading edge, driving membrane outgrowth (Figure 2B), called protrusions, which adhere to the substrate by focal contacts. Bundles of actin filaments containing myosin II motors, called

How Are Stimuli Spatially Established?

Extracellular stimuli are spatially organised to direct cells to specific locations. In this section, we examine how these signals are set up.

Mechanisms of Directional Migration

In this section, we discuss the models and molecular mechanisms at play during the directional migration of cells toward these various extracellular cues.

Many Stimuli: Common Effectors?

Many of the molecular components involved in directional migration by different types of cues have been identified. However, cells are likely to be exposed to chemical, mechanical and electrical signals altogether. For example, during wound healing, chemotactic, galvanotactic, haptotactic, and durotactic migration have all been proposed to operate. Do such diverse signals ultimately control directional cell migration by common or distinct components?

Detection of these cues is inherently

Concluding Remarks

Directional migration can be controlled by a huge range of different stimuli. There are lots of avenues for future research (see Outstanding Questions) but nonetheless common themes have emerged in the establishment, regulation, and cellular response to external cues. The in vitro evidence suggests that, theoretically, signals can be spatially established and actively shaped by both migratory cells and by other source cells. To what extent this happens in vivo is still an unaddressed question.

Acknowledgments

Work in RM laboratory is supported by grants from the Medical Research Council (MR/S007792/1), Biotechnology and Biological Sciences Research Council (M008517) and Wellcome Trust (102489/Z/13/Z).

Glossary

Arp2/3
a protein complex that acts as an actin nucleator, allowing the formation of new actin filaments from pre-existing actin filaments.
Cdc42
a small GTPase involved in filopodial protrusion formation, cell polarity, actomyosin contractility, and focal adhesion assembly [123].
Chemotaxis
directional migration along a gradient of soluble chemical cues. The first description of chemotaxis was made by Engelmann and Pfeffer in bacteria over a century ago [124,125]. Since then, repulsive and

References (152)

  • B.C. Isenberg

    Vascular smooth muscle cell durotaxis depends on substrate stiffness gradient strength

    Biophys. J.

    (2009)
  • J. Weickenmeier

    Brain stiffness increases with myelin content

    Acta Biomater.

    (2016)
  • M.J. Lee

    YAP and TAZ regulate skin wound healing

    J. Investig. Dermatol.

    (2014)
  • D. Kothapalli

    Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening

    Cell Rep.

    (2012)
  • V. Kostourou et al.

    Non-collagenous ECM proteins in blood vessel morphogenesis and cancer

    Biochim. Biophys. Acta Gen. Subj.

    (2014)
  • M. Sarris

    Inflammatory chemokines direct and restrict leukocyte migration within live tissues as glycan-bound gradients

    Curr. Biol.

    (2012)
  • J.T. Smith

    Directed cell migration on fibronectin gradients: Effect of gradient slope

    Exp. Cell Res.

    (2006)
  • S. Hsu

    Effects of shear stress on endothelial cell haptotaxis on micropatterned surfaces

    Biochem. Biophys. Res. Commun.

    (2005)
  • B.P. Nguyen

    Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion

    Curr. Opin. Cell Biol.

    (2000)
  • M. Zhao

    Electrical fields in wound healing-an overriding signal that directs cell migration

    Semin. Cell Dev. Biol.

    (2009)
  • P. Roca-Cusachs

    Mechanical guidance of cell migration: lessons from chemotaxis

    Curr. Opin. Cell Biol.

    (2013)
  • A. Shellard et al.

    Chemotaxis during neural crest migration

    Semin. Cell Dev. Biol.

    (2016)
  • I. Weber

    Is there a pilot in a pseudopod?

    Eur. J. Cell Biol.

    (2006)
  • S.V. Plotnikov

    Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration

    Cell

    (2012)
  • K.A. Lazopoulos et al.

    Durotaxis as an elastic stability phenomenon

    J. Biomech.

    (2008)
  • T. Mitchison et al.

    Cytoskeletal dynamics and nerve growth

    Neuron

    (1988)
  • C.Y. Wu

    Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis

    Cell

    (2012)
  • G.M. Allen

    Electrophoresis of cellular membrane components creates the directional cue guiding keratocyte galvanotaxis

    Curr. Biol.

    (2013)
  • Q. Liu et al.

    Electric field regulated signaling pathways

    Int. J. Biochem. Cell Biol.

    (2014)
  • K.M. Yamada et al.

    Mechanisms of 3D cell migration

    Nat. Rev. Mol. Cell Biol.

    (2019)
  • R.J. Petrie

    Random versus directionally persistent cell migration

    Nat. Rev. Mol. Cell Biol.

    (2009)
  • A.J. Ridley

    Cell migration: Integrating signals from front to back

    Science

    (2003)
  • R. Mayor et al.

    The front and rear of collective cell migration

    Nat. Rev. Mol. Cell Biol.

    (2016)
  • E.K. Paluch

    Focal adhesion-independent cell migration

    Annu. Rev. Cell Dev. Biol.

    (2016)
  • R. Pankov

    A Rac switch regulates random versus directionally persistent cell migration

    J. Cell Biol.

    (2005)
  • F. Crick

    Diffusion in embryogenesis

    Nature

    (1970)
  • E. Theveneau

    Chase-and-run between adjacent cell populations promotes directional collective migration

    Nat. Cell Biol.

    (2013)
  • A.J. Muinonen-Martin

    Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal

    PLoS Biol.

    (2014)
  • G.L. Garcia

    The group migration of Dictyostelium cells is regulated by extracellular chemoattractant degradation

    Mol. Biol. Cell

    (2009)
  • E. Dona

    Directional tissue migration through a self-generated chemokine gradient

    Nature

    (2013)
  • L. Tweedy et al.

    Self-generated gradients yield exceptionally robust steering cues

    Front. Cell Dev. Biol.

    (2020)
  • L. Tweedy

    Self-generated chemoattractant gradients: attractant depletion extends the range and robustness of chemotaxis

    PLoS Biol.

    (2016)
  • S. Lau

    A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration

    Nat. Cell Biol.

    (2020)
  • R.B. Bourret

    Signal transduction pathways involving protein-phosphorylation in prokaryotes

    Annu. Rev. Biochem.

    (1991)
  • R.H. Insall

    Understanding eukaryotic chemotaxis: a pseudopod-centred view

    Nat. Rev. Mol. Cell Biol.

    (2010)
  • S.H. Zigmond

    Ability of polymorphonuclear leukocytes to orient in gradients of chemotactic factors

    J. Cell Biol.

    (1977)
  • L. Tweedy

    Seeing around corners: cells create chemotactic gradients to solve mazes and respond to distant cues in complex environments

    bioRxiv

    (2019)
  • G. Charras et al.

    Physical influences of the extracellular environment on cell migration

    Nat. Rev. Mol. Cell Biol.

    (2014)
  • L. Bollmann

    Microglia mechanics: immune activation alters traction forces and durotaxis

    Front. Cell. Neurosci.

    (2015)
  • M. Zhu

    Spatial mapping of tissue properties in vivo reveals a 3D stiffness gradient in the mouse limb bud

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

    (2020)
  • Cited by (0)

    View full text