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Author Notes:

Correspondence to: TH Barker, Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Suite 2108, Atlanta, GA 30332-0535, USA. thomas.barker@bme.gatech.edu.

ACB, VFF, TAS and THB designed research, analyzed and interpreted data and wrote the manuscript.

ACB and VFF carried out experiments.

The authors would like to thank Wenwei Xu for assistance with AFM, Marilyn Markowski and Alison Douglas for assistance with primary ATII cell isolation, and Justin Chen for assistance with PA gel characterization.


Research Funding:

Funding was provided by the NSF ERC Georgia Tech/Emory Tissue Engineering Center (GTEC; EEC-9731643) to THB, NIH T32-GM008433 to ACB, and NSF GRFP to VFF (NSF10604).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Pathology
  • idiopathic pulmonary fibrosis
  • epithelial-to-mesenchymal transition
  • fibrosis
  • stiffness
  • cell contractility
  • alveolar epithelial cell
  • TGF-BETA-1

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

Journal Title:

Journal of Pathology


Volume 229, Number 1


, Pages 25-35

Type of Work:

Article | Post-print: After Peer Review


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

Copyright information:

© 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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