Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 18, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/ijms18112431
Keywords
pulmonary fibrosis; collagen; MMP1; matrix rigidity; TGF-; FAK; Akt; fibroblasts
Funding
- Ministerio de Economia y Competitividad (MINECO/FEDER, UE) [SAF2009-13243, PI13/02368, SAF2016-79527-R, PI060064]
- Generalitat de Catalunya AGAUR [SGR 661]
- Junta Provincial de Barcelona de l'Associacio Espanyola Contra el Cancer [AECC B16-917]
- Ministerio de Ciencia e Innovacion
- Fundacio Cellex
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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-1 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-1 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-1 that was positive for COL1A1 and negative for MMP1. Remarkably, the COL1A1 expression upregulation elicited by TGF-1 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-1 cooperate to elicit excessive collagen-I deposition in IPF, and support a major role of the FAK/Akt pathway in this cooperation.
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