Mapping the dynamics of force transduction at cell-cell junctions of epithelial clusters.

Mei Rosa Ng,Gaudenz Danuser,Joan S Brugge,Achim Besser

doi:10.7554/elife.03282

Abstract

Force transduction at cell–cell adhesions regulates tissue development, maintenance and adaptation. We developed computational and experimental approaches to quantify, with both sub-cellular and multi-cellular resolution, the dynamics of force transmission in cell clusters. Applying this technology to spontaneously-forming adherent epithelial cell clusters, we found that basal force fluctuations were coupled to E-cadherin localization at the level of individual cell–cell junctions. At the multi-cellular scale, cell–cell force exchange depended on the cell position within a cluster, and was adaptive to reconfigurations due to cell divisions or positional rearrangements. Importantly, force transmission through a cell required coordinated modulation of cell-matrix adhesion and actomyosin contractility in the cell and its neighbors. These data provide insights into mechanisms that could control mechanical stress homeostasis in dynamic epithelial tissues, and highlight our methods as a resource for the study of mechanotransduction in cell–cell adhesions [corrected].

Highlights

Tissues undergo continuous rearrangements that require tightly balanced exchanges of mechanical forces between individual cells through cadherin-mediated cell–cell junctions
Following from this, if the integrated traction force over the footprint of an individual cell within a cell cluster is non-zero, other cells in the cluster must balance it by force transmission through cell–cell adhesions
Our analyses indicated that both approaches yielded consistent results; the error for interface inverted for the calculation of mechanical stress force calculations by the finite element method (FEM) approach is compadistribution within the cell pair based on the thin-plate rable to the error we found for force calculations model, and the calculated cell internal stresses were integrated along the cell–cell junction to obtain the transmitted cell–cell stress profile along the junction

Summary

Introduction

Tissues undergo continuous rearrangements that require tightly balanced exchanges of mechanical forces between individual cells through cadherin-mediated cell–cell junctions. The importance of mechanical coupling between cells has been documented for diverse multi-cellular processes, including tissue morphogenesis during development (Mammoto and Ingber, 2010; Martin et al, 2010; Rauzi et al, 2010; Lecuit et al, 2011; Weber et al, 2012), collective migration during wound healing (Trepat et al, 2009; Tambe et al, 2011; Ng et al, 2012), epithelial and endothelial barrier functions (Tzima et al, 2005; Twiss et al, 2012), and cancer progression (Friedl et al, 2004; Bajpai et al, 2009) In all these processes, the spatiotemporal regulation of mechanical forces is essential for the maintenance of tissue integrity as well as for communication and coordination between cells. Our method expanded upon several pioneering studies, which inferred cell–cell force transmission from the regional imbalance of traction forces in cell pairs and three-cell clusters in linear configurations (Liu et al, 2010; Maruthamuthu et al, 2011; McCain et al, 2012; Tseng et al, 2012), providing the time and sub-cellular resolution needed to derive the spatiotemporal

Methods

Results

Conclusion