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Review
. 2019 Jun;100(3):144-152.
doi: 10.1111/iep.12329. Epub 2019 Jun 10.

Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis

Kenneth M Yamada  1 , Joshua W Collins  1 , David A Cruz Walma  1 , Andrew D Doyle  1 , Shaimar Gonzalez Morales  1 , Jiaoyang Lu  1 , Kazue Matsumoto  1 , Shayan S Nazari  1 , Rei Sekiguchi  1 , Yoshinari Shinsato  1 , Shaohe Wang  1
Affiliations
Review

Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis

Kenneth M Yamada et al. Int J Exp Pathol. 2019 Jun.

Abstract

This review describes how direct visualization of the dynamic interactions of cells with different extracellular matrix microenvironments can provide novel insights into complex biological processes. Recent studies have moved characterization of cell migration and invasion from classical 2D culture systems into 1D and 3D model systems, revealing multiple differences in mechanisms of cell adhesion, migration and signalling-even though cells in 3D can still display prominent focal adhesions. Myosin II restrains cell migration speed in 2D culture but is often essential for effective 3D migration. 3D cell migration modes can switch between lamellipodial, lobopodial and/or amoeboid depending on the local matrix environment. For example, "nuclear piston" migration can be switched off by local proteolysis, and proteolytic invadopodia can be induced by a high density of fibrillar matrix. Particularly, complex remodelling of both extracellular matrix and tissues occurs during morphogenesis. Extracellular matrix supports self-assembly of embryonic tissues, but it must also be locally actively remodelled. For example, surprisingly focal remodelling of the basement membrane occurs during branching morphogenesis-numerous tiny perforations generated by proteolysis and actomyosin contractility produce a microscopically porous, flexible basement membrane meshwork for tissue expansion. Cells extend highly active blebs or protrusions towards the surrounding mesenchyme through these perforations. Concurrently, the entire basement membrane undergoes translocation in a direction opposite to bud expansion. Underlying this slowly moving 2D basement membrane translocation are highly dynamic individual cell movements. We conclude this review by describing a variety of exciting research opportunities for discovering novel insights into cell-matrix interactions.

Keywords: 3D culture; basement membrane remodelling; branching morphogenesis; cell migration; extracellular matrix; invasion.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Cell migration on matrix fibres resembles one‐dimensional (1D) migration. A cell translocating along a single fibre or fibril has a very small region of contact (see the inset), which can be mimicked by engineering very narrow 1D lines on a cell culture surface and coating them with a matrix protein confined to that line [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Direct comparisons of cells migrating in 1D, 2D and 3D models in vitro. Many specific cell biological behavioural features of fibroblasts migrating within a fibronectin‐rich 3D cell‐derived matrix are mimicked by migration of these cells on fibronectin‐coated 1D lines, but not migration on 2D glass substrates coated with fibronectin or with serum proteins. Figure re‐drawn from Doyle et al28 [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Cell morphologies in 2D vs 3D collagen or 3D cell‐derived matrix environments. Cells such as human fibroblasts that migrate on flat substrates are flattened in morphology and display lamellipodia at their leading edge, which promote migration by actin polymerization and cell protrusion. The same cell type in 3D collagen gels become spindle‐shaped and display multiple tiny lamellipodia at the tip of extending cell processes at the leading edge. In 3D cell‐derived matrix, however, these cells have a more tubular shape with lateral blebs and a leading edge that lacks lamellipodia as they migrate using lobopodial migration. Cells can be switched from lobopodial to lamellipodial migration by mild proteolysis of the cell‐derived matrix. Figure re‐drawn from Petrie et al30 [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
Nuclear piston 3D cell migration. Human fibroblasts migrating within a confining 3D cell‐derived matrix switch to lobopodial migration, a migration mode in which the nucleus can serve as a piston. The nucleus is pulled forward by myosin II contractility via vimentin intermediate filaments that link to nesprin‐3 on the nucleus. This pulling forward of the nucleus pressurizes the anterior end of the cell to protrude a lobopodial process. New cell‐matrix adhesions then form at the cell anterior to anchor the cells, and the cycle can repeat with another round of nuclear piston movement [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 5
Figure 5
Invadopodia: dynamic micro‐invasive structures. Invadopodia are generated from an actin‐cortactin core at the plasma membrane and are used by cancer cells to degrade the extracellular matrix locally to promote invasion. The protease MT1‐MMP is expressed on the thin, filopodia‐like processes, which can degrade the matrix proteins and structures that they touch [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 6
Figure 6
Early step of mammalian branching morphogenesis. This example shows a mouse salivary gland with two forming clefts (narrow arrows) and forming buds expanding outward (wide arrows) into the surrounding mesenchyme
Figure 7
Figure 7
Self‐assembly of dissociated epithelial cells into bud‐like organoid structures. A, Isolated embryonic salivary gland epithelia were dissociated into single cells and then cultured within a small 3D Matrigel microenvironment on a nuclepore membrane filter. Phase‐contrast time‐lapse microscopy shows rapid self‐aggregation of the initially dissociated cells (B) into clusters that merge into large aggregates, from which bud‐like structures protrude (C) during a process of self‐organization [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 8
Figure 8
The challenge of embryonic tissue expansion within a confining basement membrane. A, The basement membrane barrier between epithelial and mesenchymal tissues must be able to expand along with bud expansion or extension during branching morphogenesis. B, Although degradation and thinning of the basement membrane are known to occur, absence of a controlled process would lead to tissue fragmentation and mixing of the highly motile epithelial cells into the surrounding mesenchyme—but this mixing does not occur in vivo. C, Basement membranes can become flexible by the formation of numerous microscopic holes or perforations that produce a lace‐like meshwork of basement membrane that can expand while still confining the epithelial cells [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 9
Figure 9
Perforated basement membrane meshwork at a bud tip. This image shows an embryonic salivary gland bud that was expanding towards the right with its basement membrane stained for collagen IV (light grey). Note the intact basement membrane on the left that becomes perforated by numerous microscopic holes (black) towards the righthand tip of an expanding bud
Figure 10
Figure 10
Basement membrane dynamics during embryonic branching morphogenesis. As buds expand outward, the basement membrane is perforated by numerous microscopic holes through which epithelial cell blebs and elongated processes protrude towards the mesenchyme. Concurrently, the entire basement membrane translocates backward towards the secondary duct [Colour figure can be viewed at wileyonlinelibrary.com]
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