Cell-matrix and cell-cell interaction mechanics in guiding migration

Abstract

Physical properties of tissue are increasingly recognised as major regulatory cues affecting cell behaviours, particularly cell migration. While these properties of the extracellular matrix have been extensively discussed, the contribution from the cellular components that make up the tissue are still poorly appreciated. In this mini-review, we will discuss two major physical components: stiffness and topology with a stronger focus on cell-cell interactions and how these can impact cell migration.

Keywords: cell migration; cell–cell interactions; mechanobiology; stiffness; tissue mechanics.

Figure 1.. The molecular clutch model of durotaxis.

Cells bias their migration towards the stiffer region due to having a higher force loading rate of integrins binding to the substrate (k_on > k_off) at the front, than at their rear (k_off > k_on). This allows more integrins to cluster at the leading front, hence higher actin polymerisation. Thicker arrows denote a higher rate than thinner arrows.

Figure 2.. The nuclear piston and nuclear compression model allow cells to migrate through a low porous environment.

Under non-constricted conditions, the nucleus has natural folds. Upon squeezing through a narrow constriction: (A) The nucleus is being pulled forwards by actomyosin contractility through Nesprin-3, which pressurises the front of the cell. This opens up ion channels such as TRPV4 or NHE, allows ions to flux into the cells, increases the osmotic pressure and draws in water. The influx of water causes the expansion of the front protrusion, which wedges open the matrix for the cell to pass through. (B) The nuclear folds are stretched, leading to the release or influx of Ca²⁺ ions into the cytoplasm through ion channels on the Endoplasmic Reticulum or on the plasma membrane. This triggers the binding of the cPLA2 enzyme to the nuclear envelope to catalyse the synthesis of Arachidonic acid, which triggers cortical actomyosin contraction and stiffens the cells to allow passing through narrow pores.

Figure 3.. The mechanism of durotaxis in vivo by neural crest.

Convergent extension causes mesodermal cells to pack together, increasing their cell density and therefore the tissue stiffness. This initiates the migration of neural crest cells. Neural crest also follows a chemotactic gradient of SDF-1 secreted by the placode. When the leading neural crest cells make contact with the placode through homotypic N-cadherin interactions, this potentially recruits RhoGAPs, which deactivates RhoA, and therefore lowers down actomyosin contractility, causes the placode to soften at the point of contact. This creates a stiffness gradient of the placode in the same direction as SDF-1, guiding the neural crest migration forwards.

Figure 4.. Guiding macrophage migration in vivo by tissue mechanics.

Macrophages invade the germ band through an opening between the layers of the ectoderm and the mesoderm. (A) TNF secreted by the surrounding cells binds to the TNF receptor (TNFR) on the ectodermal cell. This leads to the dephosphorylation of myosin, therefore lowers down cortical actomyosin contraction and softening the cell. As the first macrophage is squeezed between the ectoderm and the mesoderm, it up-regulates the transcription factor cFos, which up-regulates mRNA of actin cross-linking proteins, which then activates RhoA and Dia to increase cortical actin polymerisation and contraction. This stiffens up the macrophage and allows it to squeeze in between the two layers of tissue. (B) The ectodermal cell at the entry point adheres to the Laminin covering on top of the mesoderm layer through integrins. When this cell enters cell division, it rounds up and temporarily detaches from the Laminin. This creates an opening for the macrophage to wedge in.