Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions.

摘要: Increased tissue stiffness and epithelial-to-mesenchymal transitions (EMTs) are two seemingly discrete hallmarks of fibrotic diseases. Despite recent findings highlighting the influence mechanical properties on cell phenotype, it remains unclear what role increased has in regulation previously reported fibronectin-mediated EMTs associated with pulmonary fibrosis. Nano-indentation testing lung interstitial spaces showed that vivo cell-level Young's moduli increase onset fibrosis from ∼2 to ∼17 kPa. In vitro, we found stiff, but not soft, fibronectin substrates induce EMT, a response dependent contraction-mediated integrin activation TGFβ. Activation or suppression contractility exogenous factors was sufficient overcome effect substrate stiffness. Pulse-chase experiments indicate is dose- time-dependent. low levels TGFβ soft surfaces, either added exogenously produced through thrombin-induced contraction, cells will initiate EMT programme, upon removal revert an epithelial phenotype. These results identify matrix and/or as critical targets for novel therapeutics