Mechanosensing via cell-matrix adhesions in 3D microenvironments

Abstract

The extracellular matrix (ECM) microenvironment plays a central role in cell migration by providing physiochemical information that influences overall cell behavior. Much of this external information is accessed by direct interaction of the cell with ECM ligands and structures via integrin-based adhesions that are hypothesized to act as mechanosensors for testing the surrounding microenvironment. Our current understanding of these mechanical complexes is derived primarily from studies of cellular adhesions formed on two-dimensional (2D) substrates in vitro. Yet the rules of cell/ECM engagement and mechanosensing in three-dimensional (3D) microenvironments are invariably more complex under both in vitro and in vivo conditions. Here we review the current understanding of how cellular mechanosensing occurs through adhesion complexes within 3D microenvironments and discuss how these mechanisms can vary and differ from interactions on 2D substrates.

Keywords: 3D migration; Adhesion; Collagen; Contractility; Dynamics; Mechanotransduction.

Figure 1. Differential mechanosensing of tension in 3D

(A) Schematic representation of the effects of direction of force application in cell sensing of 3D microarchitecture. (B) For forces applied parallel or perpendicular to a fibril, the cell will perceive high or low tension, respectively. Fibril buckling and crosslinking may also play important roles in cell perceptions of tension from the surrounding ECM. (C) Within many 3D matrices, cells can interact locally with both parallel and perpendicular fibrils, which can affect adhesion size and possibly adhesion dynamics due to local perceived differences in tension.

Figure 2. 3D ECMs are not all the same

(A) Second harmonic generation (SHG: red) imaging together with immuno-labeling for mouse collagen type I (green) showing the diverse collagen microarchitectures found within a mouse ear. Inset (below) shows thick bundled fibers next to thinner loose fibrils (green) that are not detected by SHG imaging. (B and C) Collagen polymerized at 37°C (B) and 16°C (C) demonstrate different microarchitectures. Concentrations for both are 3 mg/ml. (D) An example of an aligned 3D CDM directly labeled with fluorescent dye. (E) Human dermal fibroblast transiently transfected with EGFP-talin (top and green below) migrating through a collagen gel polymerized at 16°C. Insets to the right show robust 3D adhesions at the leading edge. Scale bars: 10 μm.