Regulation of Epithelial-Mesenchymal Transition by Transmission of Mechanical Stress through Epithelial Tissues

Abstract

Epithelial-mesenchymal transition (EMT) is a phenotypic shift wherein epithelial cells lose or loosen attachments to their neighbors and assume a mesenchymal-like morphology. EMT drives a variety of developmental processes, but may also be adopted by tumor cells during neoplastic progression. EMT is regulated by both biochemical and physical signals from the microenvironment, including mechanical stress, which is increasingly recognized to play a major role in development and disease progression. Biological systems generate, transmit and concentrate mechanical stress into spatial patterns; these gradients in mechanical stress may serve to spatially pattern developmental and pathologic EMTs. Here we review how epithelial tissues generate and respond to mechanical stress gradients, and highlight the mechanisms by which mechanical stress regulates and patterns EMT.

Fig. 1

Intercellular transmission of endogenous contraction. a Cells in suspension or attached to soft matrices incapable of resisting deformation fail to generate mechanical stress. b Cells attached to a stiff substratum contract isometrically, giving rise to mechanical stress locally. c When cells are connected into cohorts, mechanical stresses generated at the single cell level are transmitted over a distance via intercellular junctions. Transmission of stress across tissues of anisotropic geometry results in concentration of stress and formation of gradients; for example, maximum stress occurs at corners of square monolayers

Fig. 2

Regulation of MRTF-A by mechanical stress. a Increased mechanical stress causes increased actin polymerization, thereby decreasing the cytoplasmic pool of G-actin and increasing the nuclear localization of MRTF-A by triggering its dissociation from G-actin. b Under conditions of low mechanical stress a larger cytoplasmic pool of G-actin sequesters MRTF-A in the cytoplasm

Fig. 3

Endogenous mechanical stress patterns EMT. a In monolayers of epithelial cells, stress is concentrated at the free edges and corners of the tissues. b Under these conditions, MRTF-A accumulates in the nuclei of cells located at the free edges and corners of the tissue, but is sequestered in the cytoplasm of cells located in the center of the tissue. c When treated with TGFβ, cells located in high stress regions undergo EMT