Physical and chemical microenvironmental cues orthogonally control the degree and duration of fibrosis-associated epithelial-to-mesenchymal transitions.
J Pathol
; 229(1): 25-35, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23018598
ABSTRACT
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 â¼2 to â¼17 kPa. In vitro, we found that stiff, but not soft, fibronectin substrates induce EMT, a response dependent on cell contraction-mediated integrin activation of TGFß. 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 TGFß 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fibrose Pulmonar
/
Mecanotransdução Celular
/
Células Epiteliais Alveolares
/
Transição Epitelial-Mesenquimal
/
Microambiente Celular
/
Pulmão
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article