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2011 ; 91
(8
): 1206-18
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Absence of Thy-1 results in TGF-? induced MMP-9 expression and confers a
profibrotic phenotype to human lung fibroblasts
#MMPMID21577212
Ramírez G
; Hagood JS
; Sanders Y
; Ramírez R
; Becerril C
; Segura L
; Barrera L
; Selman M
; Pardo A
Lab Invest
2011[Aug]; 91
(8
): 1206-18
PMID21577212
show ga
Fibroblasts differ in a variety of phenotypic features, including the expression
of Thy-1 a glycophosphatidylinositol-linked glycoprotein. Fibroblasts in
idiopathic pulmonary fibrosis (IPF) are Thy-1 negative, whereas most fibroblasts
from normal lungs are Thy-1 positive. However, the functional consequences of the
absence of Thy-1 are not fully understood. We analyzed the expression of Thy-1 in
several primary fibroblasts lines derived from IPF, hypersensitivity pneumonitis
(HP), and normal human lungs. We found that a high proportion, independently of
their origin, expressed Thy-1 in vitro. We identified a primary culture of HP
fibroblasts, which did not express Thy-1, and compared several functional
activities between Thy-1 (-) and Thy-1 (+) fibroblasts. Thy-1 (-) fibroblasts
were smaller (length: 41.3±20.8?? versus 83.1±40 ?), showed increased
proliferative capacity and enhanced PDGF-induced transmigration through collagen
I (59.9% versus 42.2% over control under basal conditions, P<0.01). Likewise,
Thy-1 (-) fibroblasts either spontaneously or after TGF-? stimulation
demonstrated stronger contraction of collagen matrices (eg, 0.17±0.03 versus
0.6±0.05 cm² after TGF-? stimulation at 24 h; P<0.01). Thy-1 (-) lung fibroblasts
stimulated with TGF-?1 expressed MMP-9, an enzyme that is usually not produced by
lung fibroblasts. TGF?-induced MMP-9 expression was reversible upon re-expression
of Thy-1 after transfection with full-length Thy-1. ?-glycan, a TGF-? receptor
antagonist abolished MMP-9 expression. TGF-?1-induced MMP-9 in Thy-1 (-)
fibroblasts depended on the activation of ERK1/2 signaling pathway. Finally, we
demonstrated that fibroblasts from IPF fibroblastic foci, which do not express
Thy-1 exhibit strong staining for immunoreactive MMP-9 protein in vivo. These
findings indicate that loss of Thy-1 in human lung fibroblasts induces a
fibrogenic phenotype.