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Review
. 2019 Sep:93:55-68.
doi: 10.1016/j.semcdb.2018.05.027. Epub 2018 Jun 1.

Adjustable viscoelasticity allows for efficient collective cell migration

Elias H Barriga  1 , Roberto Mayor  2
Affiliations
Review

Adjustable viscoelasticity allows for efficient collective cell migration

Elias H Barriga et al. Semin Cell Dev Biol. 2019 Sep.

Abstract

Cell migration is essential for a wide range of biological processes such as embryo morphogenesis, wound healing, regeneration, and also in pathological conditions, such as cancer. In such contexts, cells are required to migrate as individual entities or as highly coordinated collectives, both of which requiring cells to respond to molecular and mechanical cues from their environment. However, whilst the function of chemical cues in cell migration is comparatively well understood, the role of tissue mechanics on cell migration is just starting to be studied. Recent studies suggest that the dynamic tuning of the viscoelasticity within a migratory cluster of cells, and the adequate elastic properties of its surrounding tissues, are essential to allow efficient collective cell migration in vivo. In this review we focus on the role of viscoelasticity in the control of collective cell migration in various cellular systems, mentioning briefly some aspects of single cell migration. We aim to provide details on how viscoelasticity of collectively migrating groups of cells and their surroundings is adjusted to ensure correct morphogenesis, wound healing, and metastasis. Finally, we attempt to show that environmental viscoelasticity triggers molecular changes within migrating clusters and that these new molecular setups modify clusters' viscoelasticity, ultimately allowing them to migrate across the challenging geometries of their microenvironment.

Keywords: Adherens junctions; Cancer invasion; Collective migration; EMT; Mechanical microenvironment; Viscoelasticity.

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Figures

Fig. 1
Fig. 1
Models to study collective cell migrationin vivoand their microenvronments. A, a. Schematics of Drosophila border cell anatomical position and collective migration. (A) Border cell migration in a Drosophila embryo. (a) Border cells migrate in a confined space, surrounded by gigantic nurse cells. High levels of AJs proteins are required to resist deformation and for the mechanical feedback require for directional collective migration. B, b. Diagrams showing topographic location and confined collective migration of the posterior lateral line primordia (pLLP). (B) Initial position of the pLLP among the otic vesicle (OV) and the first somite (som 1). (b) Sagittal section showing how the pLLP migrates in a confined space between the somatic mesoderm and epidermis. Differential antero-posterior distribution of AJs is observed, while E-cadherin localises to the rear, the leading edge express a more dynamic N-cadherin. C, c. Drawings representing anatomical position and confinement during neural crest collective migration. (C) In Xenopus, cephalic neural crest migrates as a collective from dorsal towards ventral and anterior territories in well-defined streams. (c) Diagram represent a transverse section across the head of a Xenopus embryo and it shows the high degree of confinement experienced by the neural crest while migrating ‘sandwiched’ between the epidermis and underlying head mesoderm. Neural crest relies mostly in N-cadherin to mediate transient contacts require for the coordinated collective migration. Red arrows show the direction of migration for each tissue.
Fig. 2
Fig. 2
Material response to mechanical deformation. A–C. Drawings represent charts for the strain response of elastic, viscous, and viscoelastic materials to mechanical stress along time in hypothetical stress relaxation experiments. A. Elastic materials display proportional strain and stress. Elastic materials instantaneously strain upon stress and this deformation is fully and instantaneously reversed after removal of the applied stress. B. When a viscous material is stressed deformation is not instantaneous and it strain linearly with time in an irreversible manner (once applied stress is removed strain remains the same). C. Viscoelastic materials display time-dependent strain with an instantaneous elastic phase followed by time-dependent strain. Once stress is removed strain rapidly decrease as for elastic materials to then decrease, until some extent, in a time-dependent manner. Vertical dashed red lines indicate when mechanical stress is removed in the hypothetical stress relaxation experiment.
Fig. 3
Fig. 3
EMT under confinement and optimal conditions for single and collective migration. A, a. Classic model of linear EMT. (A) A sub-population of cells within an epithelia loss apicobasal polarity, undergos a switch in their cadherin content at AJs, became individual, and acquires mesenchymal migratory capabilities. When migrating in vivo, these cells are challenged by the physical strains of their surroundings. (a) The diagram shows the high degree of fluidity that a single cell reaches when migrating in confined spaces. Note that although the nucleus limits the degree of deformation that a cell can undergo, it can also deform to allow migration. (B) Schematic representation showing that for single cell migration (SCM) to occurs, cells require to acquire high degree of fluidity, which is very likely to be achieved by the extreme reduction in type-I AJs suffered during EMT. This EMT has to be highly regulated in order to maintain this low type-I cadherin levels and very importantly fluidity. Collective cell migration instead occurs just in optimal conditions of adhesion, fluidity, and EMT. In the absence of EMT an epithelial tissue has high strength of cell-cell adhesion and with that very low fluidity. If EMT is rather mild, this epithelium will maintain its epithelial behaviour with strong cell-cell adhesion mediated by type-I cadherins, this will help this tissue to resist deformation and open space to migrate in physically challenging environments (observed in wound healing or Drosophila border cell migration for instance). If the EMT rate increase, either by increasing the rate of cadherin turnover or using stronger transcriptional regulatory programs, cell clusters migrate as more fluid units that can deform in order to migrate in confined spaces (Neural crest or pLLP for instance). If the fluidity goes to a maximum, confinement and mutual attraction can help low adhesive forces to maintain collectiveness of the migratory group.
Fig. 4
Fig. 4
Collective migration and AJs remodelling can be triggered by environmental mechanics. A. The schematic shows how the mechanical interaction among migratory cell clusters and their surrounding tissues triggers AJs modification via cadherin switch. In this particular example, the tissue which is underneath a migratory cell population became stiffer as the developmental time progress. This stiffening is sensed by the migratory cell population which initiate an EMT-like program to modify their AJs in a switch from epithelial to mesenchymal type of cadherin, hence initiating fluid-like collective migration. This stiffening also provides an appropriate substrate for collective migration, where cells can efficiently polarise and form lamellipodia, required for their adherent migration. This mechanism was recently shown to trigger and support the collective migration of the Xenopus cephalic neural crest. This type of interactions may also operate in other systems where migratory substrate is observed. Stiffening in vivo has been shown to be mediated by, among other factors, actomyosin contractility, cell density, and ECM accumulation. Examples showing the elasticity ranges operating in the mechanical regulation of cadherins both, in vivo [165] and in vitro [228] are also shown.
Fig. 5
Fig. 5
Overview of the mechanical regulation of EMT and its transcription factors. While the role of well-defined families of transcription factors in the initiation of EMT is well stablished, the role of mechanics in the regulation of these transcription factors and EMT itself is just starting to be elucidated. Based on new findings this is a promising area of research with great therapeutic potential in cancer and regeneration.
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