Transcriptomic profiling reveals disease-specific characteristics of epithelial cells in idiopathic pulmonary fibrosis

Abstract

Background: Idiopathic 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. Methods: We 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. Results: Our 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. Conclusions: Our 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.

An EZH2‐dependent transcriptional complex promotes aberrant epithelial remodelling after injury

“…Recently, it has become apparent that epithelial remodelling is a key driver of IPF; however, the underlying mechanisms remain unclear (Boesch et al , 2020 ; Habermann et al , 2020 ; Selman & Pardo, 2020 ). Therefore, we focused on unveiling the pathological drivers of aberrant lung epithelial remodelling and its fibrotic consequences.…”

“…We observed an induction of aSMA levels in substituted MCs (i), consistent with injured epithelial-driven fibroblast-to-myofibroblast transition (FMT). Accordingly, replacement with untreated AECs (ii) or a combination of fresh media and MCs (iii) decreased aSMA expression in MCs (Fig 1G Recently, it has become apparent that epithelial remodelling is a key driver of IPF; however, the underlying mechanisms remain unclear (Boesch et al, 2020;Habermann et al, 2020;Selman & Pardo, 2020). Therefore, we focused on unveiling the pathological drivers of aberrant lung epithelial remodelling and its fibrotic consequences.…”

The use of cultured human alveolar basal cells to mimic honeycomb formation in idiopathic pulmonary fibrosis

“…Although, our models may not fully reflect the in vivo situation of IPF HC, they appear superior to previously used models (22, 25) as BC, used in this study, 1) are IPF patient-derived and 2) were isolated from fibrotic IPF parenchyma, and not from the airways. Using cells from patient-derived tissue and from the region of interest seems important as it was shown that cells maintain disease- and region-specific characteristics when cultured in vitro (27, 28). Although our current study does not provide new insights into the origin or function of alveolar BC in IPF, the use of the here presented models in future studies will greatly enhance our knowledge about the role of alveolar BC in HC formation and its potential pharmacological inhibition in IPF.…”

Mesenchymal Stem/Stromal Cells in Progressive Fibrogenic Involvement and Anti-Fibrosis Therapeutic Properties

“…Primary lung-resident MSCs can be isolated from patients with idiopathic pulmonary fibrosis (IPF), a progressive lung disease of unknown etiology, and the increased number of MSCs accompanied by the augmented ECM deposition has been observed in the lung interstitium ( Hostettler et al, 2017 ; Boesch et al, 2020 ). Lung-resident MSCs have been also shown to undergo phenotype conversion, for example, to myofibroblasts in vivo , and to increase ECM products contributing to pulmonary fibrogenesis ( Chen et al, 2018 ; Cao et al, 2020 ).…”