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Epithelial contribution to the profibrotic stiff microenvironment and
myofibroblast population in lung fibrosis
#MMPMID29046395
Gabasa M
; Duch P
; Jorba I
; Giménez A
; Lugo R
; Pavelescu I
; Rodríguez-Pascual F
; Molina-Molina M
; Xaubet A
; Pereda J
; Alcaraz J
Mol Biol Cell
2017[Dec]; 28
(26
): 3741-3755
PMID29046395
show ga
The contribution of epithelial-to-mesenchymal transition (EMT) to the profibrotic
stiff microenvironment and myofibroblast accumulation in pulmonary fibrosis
remains unclear. We examined EMT-competent lung epithelial cells and lung
fibroblasts from control (fibrosis-free) donors or patients with idiopathic
pulmonary fibrosis (IPF), which is a very aggressive fibrotic disorder. Cells
were cultured on profibrotic conditions including stiff substrata and TGF-?1, and
analyzed in terms of morphology, stiffness, and expression of EMT/myofibroblast
markers and fibrillar collagens. All fibroblasts acquired a robust myofibroblast
phenotype on TGF-?1 stimulation. Yet IPF myofibroblasts exhibited higher
stiffness and expression of fibrillar collagens than control fibroblasts,
concomitantly with enhanced FAK(Y397) activity. FAK inhibition was sufficient to
decrease fibroblast stiffness and collagen expression, supporting that FAK(Y397)
hyperactivation may underlie the aberrant mechanobiology of IPF fibroblasts. In
contrast, cells undergoing EMT failed to reach the values exhibited by IPF
myofibroblasts in all parameters examined. Likewise, EMT could be distinguished
from nonactivated control fibroblasts, suggesting that EMT does not elicit
myofibroblast precursors either. Our data suggest that EMT does not contribute
directly to the myofibroblast population, and may contribute to the stiff
fibrotic microenvironment through their own stiffness but not their collagen
expression. Our results also support that targeting FAK(Y397) may rescue normal
mechanobiology in IPF.
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