Document Detail


Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial to mesenchymal transition.
MedLine Citation:
PMID:  23018598     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Increased tissue stiffness and epithelial to mesenchymal transitions (EMT) 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 EMT associated with pulmonary fibrosis. Nanoindentation testing of lung interstitial spaces showed that in vivo cell-level Young's moduli increase with the onset of fibrosis from 2kPa to 17kPa. 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 program, 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 © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Authors:
Ashley C Brown; Vincent F Fiore; Todd A Sulchek; Thomas H Barker
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-28
Journal Detail:
Title:  The Journal of pathology     Volume:  -     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Affiliation:
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta GA 30332.
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