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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

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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 4

Converging and independent modulation of ECM gene translation is dependent upon ECM and cell origins.

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Converging and independent modulation of ECM gene translation is depende...
(A) Translation (ANOTA-corrected) and steady-state RNA profiles of genes in the ECM region gene ontology that were differentially expressed (P < 0.05) in any comparison. Values are log10P values (yellow denotes upregulation in IPF, blue denotes downregulation). (B) Close-up of the translation profile. Genes are divided into three categories: cell-regulated, ECM-regulated, and coregulated. Density plots of the absolute fold changes induced by each biological variable are shown. Selected gene ontologies that are overrepresented (P < 0.01, calculated using Fisher’s exact test) are shown (see Supplemental Table 2 for the complete list). There were no significantly overrepresented gene ontologies in the cell-regulated group. (C) Same analysis for the steady-state RNA profile.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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