Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is an incurable disease characterized by progressive lung fibrosis ultimately resulting in respiratory failure and death. Recurrent micro-injuries to the alveolar epithelium and aberrant alveolar wound healing with impaired re-epithelialization define the initial steps of the pathogenic trajectory. Failure of timely alveolar epithelial repair triggers hyper-proliferation of mesenchymal cells accompanied by increased deposition of extracellular matrix into the lung interstitium.MethodsWe previously isolated fibrosis-specific mesenchymal stem cell (MSC)-like cells from lung tissue of patients with interstitial lung diseases. These cells produced factors bearing anti-fibrotic potential and changed their morphology from mesenchymal to epithelial upon culture in an epithelial cell (EC)-specific growth medium. Here, we set out to molecularly characterize these MSC-like cell-derived ECs using global gene expression profiling by RNA-sequencing. Moreover, we aimed at characterizing disease-specific differences by comparing the transcriptomes of ECs from IPF and non-IPF sources.ResultsOur results suggest that differentially expressed genes are enriched for factors related to fibrosis, hypoxia, bacterial colonization and metabolism, thus reflecting many of the hallmark characteristics of pulmonary fibrosis. IPF-ECs showed enrichment of both pro- and anti-fibrotic genes, consistent with the notion of adaptive, compensatory regulation.ConclusionsOur findings support the hypothesis of a functional impairment of IPF-ECs, which could possibly explain the poor clinical outcome of IPF that roughly compares to those of advanced-stage cancers. Our study provides a valuable resource for downstream mechanistic investigation and the quest for novel therapeutic IPF targets.
Highlights
Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterized by progressive lung fibrosis resulting in respiratory failure and death
The underlying pathomechanisms are incompletely understood, it is generally believed that ongoing damage to the alveolar epithelium triggers a secondary fibrotic response in lung-resident fibroblasts that further impinges on lung function [4, 5]; formal support for this concept for IPF pathogenesis came from mechanistic studies in mice [6, 7]
While we previously showed that mesenchymal stem cell (MSC)-like cells exhibit epithelial cell (EC) morphology when cultured in an EC-specific growth
Summary
Idiopathic pulmonary fibrosis (IPF) is an incurable disease characterized by progressive lung fibrosis resulting in respiratory failure and death. Failure of timely alveolar epithelial repair triggers hyper-proliferation of mesenchymal cells accompanied by increased deposition of extracellular matrix into the lung interstitium. Idiopathic pulmonary fibrosis (IPF) is an incurable interstitial lung disease (ILD) characterized by progressive fibrosis and worsening dyspnea, leading to respiratory failure and death [1, 2]. MSClike cells changed their mesenchymal look to a bona fide (cobblestone-like) epithelial morphology when cultured in epithelial cell (EC)-specific growth medium. This distinct change in morphology was paralleled by induction of E-cadherin (CD324) expression, a canonical marker of ECs [5]
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