Impact of Transcriptomics on Our Understanding of Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrotic lung disease characterized by aberrant remodeling of the lung parenchyma with extensive changes to the phenotypes of all lung resident cells. The introduction of transcriptomics, genome scale profiling of thousands of RNA transcripts, caused a significant inversion in IPF research. Instead of generating hypotheses based on animal models of disease, or biological plausibility, with limited validation in humans, investigators were able to generate hypotheses based on unbiased molecular analysis of human samples and then use animal models of disease to test their hypotheses. In this review, we describe the insights made from transcriptomic analysis of human IPF samples. We describe how transcriptomic studies led to identification of novel genes and pathways involved in the human IPF lung such as: matrix metalloproteinases, WNT pathway, epithelial genes, role of microRNAs among others, as well as conceptual insights such as the involvement of developmental pathways and deep shifts in epithelial and fibroblast phenotypes. The impact of lung and transcriptomic studies on disease classification, endotype discovery, and reproducible biomarkers is also described in detail. Despite these impressive achievements, the impact of transcriptomic studies has been limited because they analyzed bulk tissue and did not address the cellular and spatial heterogeneity of the IPF lung. We discuss new emerging technologies and applications, such as single-cell RNAseq and microenvironment analysis that may address cellular and spatial heterogeneity. We end by making the point that most current tissue collections and resources are not amenable to analysis using the novel technologies. To take advantage of the new opportunities, we need new efforts of sample collections, this time focused on access to all the microenvironments and cells in the IPF lung.

Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis

“…The use of informatics-based analysis of gene expression data to identify genes, pathways and mechanisms of relevance in organs and tissues of interest has become an established path to uncovering important pathobiology. [19] scRNAseq methodologies are rapidly advancing and recent studies have provided important insights into the heterogeneity and diversity of mesenchymal, epithelial and alveolar macrophage populations in the setting of pulmonary fibrosis. [20–22] However, spatial information, and therefore the precise anatomical location from which the cells are derived, is lost during single cell dissociation.…”

Biobanking and cryopreservation of human lung explants for omic analysis

“…High throughput molecular studies have yielded valuable insights into lung pathobiology, yet many studies are limited by low sample number and lack validation cohorts [17]. Individuals diagnosed with the same disease may have widely disparate clinical courses and responses to therapies, underscoring the need to generate biorepositories with comprehensive cellular and molecular phenotyping that can facilitate personalised approaches to disease classification and management.…”

Chaotic activation of developmental signalling pathways drives idiopathic pulmonary fibrosis

“…Those features could be just the consequence of stochastic events and disorganisation. However, several transcriptomic analyses showed that IPF could be classified and separated from other interstitial lung fibrotic diseases, suggesting that underlying patterns and laws do drive this disease [11]. In the present article, we will examine whether an aberrant transcriptional integration of those pathways may be involved honeycombing; and 4) hyperplastic alveolar epithelial type 2 cell (AE2C) (lower image is a magnification of the dashed box).…”

“…Thus, small changes in the dynamic of developmental signalling networks in chronically injured lungs may have major impacts on the different lung cell populations leading to the generation of diverse and even atypical phenotypes. Indeed, single-cell transcriptomic methods applied to the fibrotic lung identified an alveolar epithelial cell population with mixed differentiation state [11,37].…”