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

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.

Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injury

“…Increased clearance of collagen type I by either WFA or collagen type I siRNA decreased invasiveness of IPF fibroblasts. Collagen type I regulates invasiveness of cells by various mechanisms in IPF (50,51,54,55). Collagen interacts with integrin (56,57), which can affect invasiveness of the cells in ECM (58).…”

Analysis of the Interaction Network of Hub miRNAs-Hub Genes, Being Involved in Idiopathic Pulmonary Fibers and Its Emerging Role in Non-small Cell Lung Cancer

“…were considered to be significantly related to IPF and NSCLC. Focal adhesion was considered as a key pathway shared by blue module and turquoise module, and many gens/proteins have been considered to be involved in the progression of IPF through disordering focal adhesion (Gimenez et al, 2017;Kathiriya et al, 2017;Molina-Molina et al, 2018). For example, it has been reported that decreased expression of collagen VI, an important kind of protein of ECM, would upregulate the focal adhesion (Knueppel et al, 2018).…”

TGF‑β1 induces CREB1‑mediated miR‑1290 upregulation to antagonize lung fibrosis via Napsin�A

“…Previous studies have demonstrated that TGF-β1 is related to the AKT pathway in PF (27), lung cancer (28), live fibrosis (29). Based on this, the present study examined the association between TGF-β1 and the AKT pathway in A549 cells under TGF-β1 stimulation.…”