Fibrotic extracellular matrix activates a profibrotic positive feedback loop
Matthew W. Parker, … , Ola Larsson, Peter B. Bitterman
Matthew W. Parker, … , Ola Larsson, Peter B. Bitterman
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(4):1622-1635. https://doi.org/10.1172/JCI71386.
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Research Article Pulmonology

Fibrotic extracellular matrix activates a profibrotic positive feedback loop

Abstract

Pathological remodeling of the extracellular matrix (ECM) by fibroblasts leads to organ failure. Development of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive fibrotic scarring in the lung that ultimately leads to asphyxiation; however, the cascade of events that promote IPF are not well defined. Here, we examined how the interplay between the ECM and fibroblasts affects both the transcriptome and translatome by culturing primary fibroblasts generated from IPF patient lung tissue or nonfibrotic lung tissue on decellularized lung ECM from either IPF or control patients. Surprisingly, the origin of the ECM had a greater impact on gene expression than did cell origin, and differences in translational control were more prominent than alterations in transcriptional regulation. Strikingly, genes that were translationally activated by IPF-derived ECM were enriched for those encoding ECM proteins detected in IPF tissue. We determined that genes encoding IPF-associated ECM proteins are targets for miR-29, which was downregulated in fibroblasts grown on IPF-derived ECM, and baseline expression of ECM targets could be restored by overexpression of miR-29. Our data support a model in which fibroblasts are activated to pathologically remodel the ECM in IPF via a positive feedback loop between fibroblasts and aberrant ECM. Interrupting this loop may be a strategy for IPF treatment.

Authors

Matthew W. Parker, Daniel Rossi, Mark Peterson, Karen Smith, Kristina Sikström, Eric S. White, John E. Connett, Craig A. Henke, Ola Larsson, Peter B. Bitterman

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Figure 5

A positive feedback loop between diseased ECM and the fibroblast involves modulation of miR-29 expression.

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A positive feedback loop between diseased ECM and the fibroblast involve...
(A) Translation profile of genes whose protein products are present in IPF lung ECM. Shown are –log10P values from the cell origin and ECM origin comparison (yellow denotes upregulation in IPF, blue denotes downregulation). miR-29 targets are designated by solid bars above the heatmap. (B and C) Cumulative P value probability distributions for (B) ECM origin and (C) cell origin are shown. Dotted line represents the theoretical null distribution. Black line represents all genes except ECM region genes. Red line represents all ECM genes except those detected in the IPF lung (KS P value for comparison with “All genes”). Blue line represents all genes from the IPF lung except miRNA-29 targets (KS P value for comparison with “ECM genes”). Yellow line represents all IPF-detected miR-29 targets (KS P value for comparison with “IPF-detected proteins”). (D and E) Levels of miR-29 species were quantified using qPCR. In all comparisons, the arbitrary units were normalized to the control level. The levels of miR-29c between control and IPF ECM were significantly altered (P = 0.031). It should be noted that the ECM comparison is paired so the single error bar represents the standard error between the paired differences.