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Int. J. Mol. Sci. 2017, 18(11), 2431; doi:10.3390/ijms18112431

Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-β1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt

1
Unit of Biophysics and Bioengineering, Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08036 Barcelona, Spain
2
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
3
Pneumology Service, Hospital Clínic, 08036 Barcelona, Spain
4
CIBER de Enfermedades Respiratorias (CIBERES), 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Received: 11 October 2017 / Revised: 3 November 2017 / Accepted: 7 November 2017 / Published: 16 November 2017
(This article belongs to the Special Issue TGF-beta Family in Fibrosis and Cancer)
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Abstract

Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which normal lung parenchyma is replaced by a stiff dysfunctional scar rich in activated fibroblasts and collagen-I. We examined how the mechanochemical pro-fibrotic microenvironment provided by matrix stiffening and TGF-β1 cooperates in the transcriptional control of collagen homeostasis in normal and fibrotic conditions. For this purpose we cultured fibroblasts from IPF patients or control donors on hydrogels with tunable elasticity, including 3D collagen-I gels and 2D polyacrylamide (PAA) gels. We found that TGF-β1 consistently increased COL1A1 while decreasing MMP1 mRNA levels in hydrogels exhibiting pre-fibrotic or fibrotic-like rigidities concomitantly with an enhanced activation of the FAK/Akt pathway, whereas FAK depletion was sufficient to abrogate these effects. We also demonstrate a synergy between matrix stiffening and TGF-β1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-β1 alone or synergistically with matrix stiffening were higher in IPF-fibroblasts compared to control fibroblasts in association with larger FAK and Akt activities in the former cells. These findings provide new insights on how matrix stiffening and TGF-β1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation. View Full-Text
Keywords: pulmonary fibrosis; collagen; MMP1; matrix rigidity; TGF-β; FAK; Akt; fibroblasts pulmonary fibrosis; collagen; MMP1; matrix rigidity; TGF-β; FAK; Akt; fibroblasts
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MDPI and ACS Style

Giménez, A.; Duch, P.; Puig, M.; Gabasa, M.; Xaubet, A.; Alcaraz, J. Dysregulated Collagen Homeostasis by Matrix Stiffening and TGF-β1 in Fibroblasts from Idiopathic Pulmonary Fibrosis Patients: Role of FAK/Akt. Int. J. Mol. Sci. 2017, 18, 2431.

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