Cell migration

Abstract

Cell migration is fundamental to establishing and maintaining the proper organization of multicellular organisms. Morphogenesis can be viewed as a consequence, in part, of cell locomotion, from large-scale migrations of epithelial sheets during gastrulation, to the movement of individual cells during development of the nervous system. In an adult organism, cell migration is essential for proper immune response, wound repair, and tissue homeostasis, while aberrant cell migration is found in various pathologies. Indeed, as our knowledge of migration increases, we can look forward to, for example, abating the spread of highly malignant cancer cells, retarding the invasion of white cells in the inflammatory process, or enhancing the healing of wounds. This article is organized in two main sections. The first section is devoted to the single-cell migrating in isolation such as occurs when leukocytes migrate during the immune response or when fibroblasts squeeze through connective tissue. The second section is devoted to cells collectively migrating as part of multicellular clusters or sheets. This second type of migration is prevalent in development, wound healing, and in some forms of cancer metastasis.

Figure 1

Different types of cell migration. (A) A stationary, spread C3H10T1/2 fibroblast triple stained with DAPI (blue) for DNA, MitoTracker (red) for mitochondria, and Alexa Fluor phalloidin (94) for F-actin. (B) Fibroblasts migrating into wound. Top: initially, a wound was made in a confluent monolayer of MDA-MB-231cells by scratching using a pipette tip. Bottom: after 15 h, migrating cells began to fill in the wound (120). (C) Migrating zebrafish keratocytes with large fan-like lamellipodia. (D) An HL-60 cell (human promyelocytic leukemia cell) migrating on a glass substrate after differentiation with dimethyl sulfoxide (DMSO) to exhibit leukocyte-like behavior on glass substrate. (Image in 1A and 1D are courtesy of Bing Yang and Zenon Rajfur, respectively.) Scale bars in A, C, and D are 10 μm, in B is 100 um.

Figure 2

Adhesion structure and function in cells. (A) An immunofluorescence image of focal adhesions (FAs) in an NIH 3T3 cell stained with antipaxillin; (B) an interference reflection microscopy (IRM) image of FAs in a similar NIH 3T3 fibroblast on a fibronectin (FN)-coated substrate; the very dark regions (arrows) are FAs; and (C) schematic figure for the relationship between cell adhesion, cell migration, and some of the corresponding adaptor and signal proteins. Cell matrix adhesion complexes are depicted a key component in single-cell adhesion and migration. After activation, integrins bind extracellular matrix (ECM) and provide a link to the actin cytoskeleton. Cytoplasmic adaptor proteins bind integrin cytoplasmic domains, stabilize FA, and provide scaffolding functions. Integrin activation also initiates downstream signaling. Such signaling may regulate cell adhesion turnover, internal force development, and cytoskeletal rearrangements including formation of stress fibers, lamellipodia, filopodia, and podosomes. Cell migration also involves both ECM degradation and proteolysis and adhesion complex internalization (see section on focal adhesion dynamics). Scale bars in A and B are 10 μm.

Figure 3

(A) Interference reflection microscopy (IRM) image of close adhesion in migrating fish kera-tocytes, the adhesion pattern consists of an outer rim (r) of very close contact skirting a crescent-shaped band of alternating very close (v) and distant contacts (d). (B) Epifluorescent image of podosomes in a human dendritic cell with F-actin labeling. (C) A hypothetical view of close contacts in which small diameter projections attach to the substrate and serve to draw the ventral surface closer to the substrate such that it appears gray in IRM. Integrin, talin, F-actin have been reported to be in close adhesions [in this schematic, the actin network is depicted like that in a microvillus with parallel actin bundles but it could also be in the form of a dendritic actin network (not shown)]; however, paxillin and focal adhesion kinase (FAK) are not found in initial close contacts. Scale bars are 10 μm. Image in panel A is from Lee and Jacobson (158); image in panel B is courtesy of Aaron Neumann.

Figure 4

Use of elastic substrates to map tractions in migrating cells. (A) Phase image showing a fish keratocytes crawling on an elastic polyacrylamide substrate. (B) Tractions mapped on the same cell shown in A. The Dembo Boundary element method algorithm (52) was used to calculate the cell traction distribution from the bead displacement map; the units in the map are in Dynes/cm² (1 dyne = 10⁻⁵N). (C) The Fourier-transform traction cytometry (FTTC) algorithm (28) was used to calculate tractions for another keratocyte; the right scale of color bar represents stress in units of Pa (1 Pa = 1 N/m²). Scale bar is 10 μm. Images are courtesy of Zenon Rajfur.

Figure 5

Collective cell migration in development. (A-D) During development of the abdomen of Drosophila melanogaster a cluster of histoblasts (green arrow) grows and migrates radially outward at the expense of the surrounding larval cells. Courtesy of Enrique Martin-Blanco and Carla Prat. (E–F) During development of the sensory system of zebrafish, the lateral line primordium undergoes directed migration from head to tail, leaving behind rosettes (red arrows) at periodic intervals. Scale bars: 60 μm. Courtesy of Hernan Lopez-Schier and Filipe Pinto.

Figure 6

Collective cell migration in cancer. (A) Different invasion patterns in primary melanoma invading the mid-dermis in vivo. Arrowheads indicate scattered individual cells. Collective invasion modes include solid stands (Str), nests (N) representing cross-sectioned strands, and single cell chains (IF, “Indian files”). H&E staining. Image modified, with permission, from Friedl and Wolf (78). (B) Invasion modes in a modified skin-fold chamber model of orthotopic invasion of human HT-1080 fibrosarcoma cells. Patterns include lack of invasion (top, left), disseminating single cells (top, right), and diffuse or compact strand-like collective invasion (lower panels). Bar 250 μm. (C) Frequency of invasion modes displayed in B. Adapted, with permission, from Alexander et al. (7).

Figure 7

Scheme depicting the key molecules that mediate cell-cell adhesion during collective cell migration.

Figure 8

Mechanics of collective cell migration. (A) The forces exerted by the leading edge of an MDCK epithelial cell sheet migrating on top of a microneedle array are tensile. Adapted, with permission, from reference . (B, C, D) Patterns of force generation and transmission in an epithelial cell sheet. (B) An active leader cell generates forces at the leading edge and transmits these forces to follower cells via cell-cell junctions. (C) Each cell within the monolayer generates its own contractile forces. Forces are balanced locally in such a way that there is no force transmission through cell-cell junctions. (D) Tug-of-war force generation and transmission. The local tractions that each cell generates are transmitted through cell-cell junctions to generate a global gradient of tensile stress. (E) Phase contrast image of an MDCK cell sheet advancing on top of a soft polyacrylmide gel (1.2 kPa). In this model, tractions parallel (F) and perpendicular (G) to the leading edge rule out the existence of leader/follower polarity.