Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues

Abstract

Directed cell migration is a complex process that involves front-rear polarization, characterized by cell adhesion and cytoskeleton-based protrusion, retraction, and contraction of either a single cell or a cell collective. Single cell polarization depends on a variety of mechanochemical signals including external adhesive cues, substrate stiffness, and confinement. In cell ensembles, coordinated polarization of migrating tissues results not only from the application of traction forces on the extracellular matrix but also from the transmission of mechanical stress through intercellular junctions. We focus here on the impact of mechanical cues on the establishment and maintenance of front-rear polarization from single cell to collective cell behaviors through local or large-scale mechanisms.

Keywords: cell forces; cell polarity; collective cell migration; mechanobiology; micropatterning; substrate stiffness.

Figure I. Properties of Passive Systems.

(A) Response of polymer networks under directional external constraint. (B) Examples of phase transitions in liquid crystal materials in response to external stimuli including apolar and polar particles.

Figure I. Basic Rheological Models.

For the Voigt solid, the system does not undergo any deformation at long time scales. It is represented by a purely viscous damper and a purely elastic component connected in parallel. For the Maxwell liquid, the system flows as a liquid over long periods of time. It is represented by a purely viscous damper and a purely elastic component connected in series.

Figure I. Actin Architecture in a Single Migrating Cell including Actin Cortex, Lamellipodia, and Different Types of Stress Fibers.

Actin organization within the cell and its link to filament ordering. Ventral stress fibers: antiparallel filaments and contribution of both active and passive stresses to contractility. Organization of branched actin network in lamellipodial structures.

Figure 1. Single Cell Polarization by Biomechanical Cues.

(Left) Circular shape of a single cell under various conditions with the formation of noncontractile actin radial fibers at the edge and transverse arcs at the back (actin filaments are in dark red). Microtubules (MTs; orange) are confined in the central region. Light red dots represent focal adhesions (FAs) and black arrows represent the direction of the actin retrograde flow. (Middle) Appearance of ventral stress fibers that are organized in local domains on substrate of intermediate stiffness. The order parameter, S, that characterizes actin orientation is low. Note MTs reaching the edge of the cells. (Right) Actin polarization characterized by a large-scale alignment of actin filaments on stiff substrates, at long time scales and/or on fibronectin-coated surfaces (S = 1).

Figure 2. Response of Single Cell Actomyosin and Microtubule (MT) Organization to Adhesion and Mechanical Cues.

(A) Rat embryonic fibroblast (REF52) cells seeded on soft and stiff fibronectin-coated surfaces (M. Gupta et al., unpublished) [61]. (B) Double staining for F-actin (red) and MTs (green) of C2C12 cells spread on N-cadherin or fibronectin substrates [61]. (C) Aplysia growth stirred for 4 min with an adhesion molecule-coated bead was stained for F-actin (red) and MTs (green) [67]. Scale bars: A,B = 20 µm; C = 5 µm.

Figure 3. Mechanisms of Collective Cell Polarization by Mechanical Cues.

(A) Cells polarize downstream of a gradient of intercellular tension at the leading edge of expanding cell monolayers. (B) Cell doublets repolarize away from their intercellular contact. Under certain conditions, such repolarization leads to cell repulsion through contact inhibition of locomotion (CIL) interactions. (C) Spontaneous polarization of cell clusters and swirls within cohesive monolayers. These polarized structures emerge as a function of cell density, tension fluctuations, and confinement. (D) Contractile cables lining the leading front of cell monolayers coordinate cell polarization and Rho-GTPase activation at a supracellular length scale. (E) Contractile cables coordinate cell polarization at the leading front of a wound.