Cadherin-based intercellular adhesions organize epithelial cell–matrix traction forces

Abstract

Cell-cell and cell-matrix adhesions play essential roles in the function of tissues. There is growing evidence for the importance of cross talk between these two adhesion types, yet little is known about the impact of these interactions on the mechanical coupling of cells to the extracellular matrix (ECM). Here, we combine experiment and theory to reveal how intercellular adhesions modulate forces transmitted to the ECM. In the absence of cadherin-based adhesions, primary mouse keratinocytes within a colony appear to act independently, with significant traction forces extending throughout the colony. In contrast, with strong cadherin-based adhesions, keratinocytes in a cohesive colony localize traction forces to the colony periphery. Through genetic or antibody-mediated loss of cadherin expression or function, we show that cadherin-based adhesions are essential for this mechanical cooperativity. A minimal physical model in which cell-cell adhesions modulate the physical cohesion between contractile cells is sufficient to recreate the spatial rearrangement of traction forces observed experimentally with varying strength of cadherin-based adhesions. This work defines the importance of cadherin-based cell-cell adhesions in coordinating mechanical activity of epithelial cells and has implications for the mechanical regulation of epithelial tissues during development, homeostasis, and disease. mechanotransduction | traction force microscopy M echanical interactions of individual cells have a crucial role in the spatial organization of tissues (1, 2) and in embryonic development (3-5). The mechanical cooperation of cells is evident in dynamic processes such as flow-induced alignment of vascular endothelial cells (6) and muscle contraction (7). However, mechanical interactions of cells within a tissue also affect the tissue's static mechanical properties including elastic modulus (8), surface tension (9), and fracture toughness (10). Little is known about how these tissue-scale mechanical phenomena emerge from interactions at the molecular and cellular levels (11).Tissue-scale mechanical phenomena are particularly important in developmental morphogenesis (12), homeostasis (13), and wound healing (14) in epithelial tissues. Cells exert mechanical force on each other at sites of intercellular adhesion, typically through cadherins (15, 16), as well as on the underlying extracellular matrix (ECM) through integrins (17-19). Cadherin-based adhesions can alter physical aspects of cells such as the surface tension of cellular aggregates (20) and the spreading (21) and migration (22) of single cells adherent to cadherin-patterned substrates. Integrity of intercellular adhesions may also contribute to metastatic potential (23). We and others have shown that epithelial cell clusters with strong cell-cell adhesions exhibit coordinated mechanical behavior over length scales much larger than a single cell (24-27). Several studies have implicated cross talk between cell-ECM and cell-cell adhesions (28, 29) that can be modulated by ac...

Propagating Stress Waves During Epithelial Expansion

“…The assumption of elasticity is supported by experimental evidence that in cohesive cell layers stress and strain tend to be in phase, as in elastic materials [7,8]. The contractile units represent actomyosin assemblies that locally generate contractile stresses in the cells.…”

“…Many developmental processes, such as embryogenesis [1], tissue morphogenesis [2], wound healing [3] and cancer metastasis [4], involve collective cell migration [5] and long-scale force generation, which in turn rely on the interplay of cell-cell cohesion, cell adhesion to the extracellular matrix, as well as myosin based contractility [6,7]. Recent experiments reveal that unconstrained tissue expansion is accompanied by propagating mechanical waves and build-up of intercellular stresses [8].…”

Investigating cell mechanics with atomic force microscopy

“…The mechanical properties of the ECM have long been known to influence cell behaviour, such as motility [39], and fate, as demonstrated by the influence of substrate stiffness on differentiation [40,41]. Sites of ECM-cell adhesion (FAs) [42], as well as cell -cell adhesion (cadherins) [43], are also directly affected by ECM composition and are known regions of force sensing and transmission. Classically, a mechanosensor was defined as a transmembrane ion channel linked via tethered networks to both intra-and extracellular anchors [44].…”

Force Measurement Tools to Explore Cadherin Mechanotransduction

“…Interestingly, concentration and presence of cadherin binding did not affect migration rate of the cells but did infl uence directional bias, and without ECM presence cell migration was absent. A similar rearrangement of ECM-applied traction force directionality was observed in keratinocyte colonies when cell -cell adhesion formation was initiated in the presence of calcium (Mertz et al, 2013). Such forcedependent cross-talk between cell -cell and cell -ECM adhesion molecules seems to suggest that both physical and biochemical regulatory pathways play a role in coordinating these two systems.…”