The spatial patterning of cellular behaviors plays an important role during tissue development, differentiation, and wound healing. Localized patterns may result from a variety of stimuli, including concentration gradients of diffusible factors (morphogens), adhesion to the extracellular matrix, and mechanical forces [Nelson, 2009
]. Endogenous (cell-generated) mechanical stresses arising from isometric cytoskeletal tension are transmitted within tissues between cells, their neighbors, and the surrounding extracellular matrix. In culture, gradients in mechanical stress can arise as a result of the geometry of the tissue, with free edges or areas of high curvature experiencing the greatest stress [Nelson et al., 2005
]. Mechanical stress has been increasingly implicated as a key regulator of a wide range of cellular behaviors, including proliferation [Nelson et al., 2005
], stem cell lineage commitment [Engler et al., 2006
], and the tumorigenic phenotype [Paszek et al., 2005
Epithelial-mesenchymal transition (EMT) is a phenotypic shift that governs a variety of morphogenetic processes, including gastrulation, neural crest development, and heart valve formation [Thiery et al., 2009
]. During EMT, epithelial cells loosen attachments to their neighbors, acquire a mesenchymal-like morphology and become motile. These phenotypic changes are accompanied by alterations in gene expression patterns, including attenuation of epithelial markers (such as epithelial cytokeratins and E-cadherin) and neo-expression of mesenchymal markers (such as vimentin and α-smooth muscle actin (αSMA)) [Zeisberg and Neilson, 2009
]. Developmental EMTs occur at specific times and locations to ensure proper patterning of the embryo (reviewed in [Shook and Keller, 2003
]). Pathologic EMTs can also be spatially patterned, having been observed at the edges of wounds and the invasive front of metastatic lesions [Arnoux et al., 2005
; Oft et al., 1998
]. EMT can be induced by soluble stimuli including cytokines, growth factors, and metalloproteinases [Thiery et al., 2009
], but mechanisms for spatially patterning EMT are largely unexplored.
Here, we investigated the spatial patterning of EMT in two-dimensional (2D) sheets of epithelial cells. We found that when treated with transforming growth factor (TGF)-β, microfabricated monolayers of mammary epithelial cells of defined shape and size underwent EMT preferentially at specific locations, notably the edges and corners of square sheets. Given that endogenous mechanical stress was concentrated in these regions, we explored how cell-cell contact and the transmission of intercellular tension affected TGFβ-induced EMT. We demonstrated that spatial patterning of EMT can result from endogenous gradients in mechanical stress, suggesting a role for the physical microenvironment in the regulation of EMT.