Insights Into Development and Progression of Idiopathic Pulmonary Fibrosis From Single Cell RNA Studies

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options. The current model suggests that chronic or repetitive “micro-injuries” of the alveolar epithelium lead to activation and proliferation of fibroblasts and excessive extracellular matrix (ECM) deposition. Disruption of alveolar type II (ATII) epithelial cell homeostasis and the characteristics of mesenchymal cell populations in IPF have received particular attention in recent years. Emerging data from single cell RNA sequencing (scRNAseq) analysis shed novel light on alterations in ATII cell progenitor dysfunction and the diversity of mesenchymal cells within the fibrotic lung. Within this minireview, we summarize the data from most recent human scRNAseq studies. We aim to collate the current knowledge on cellular plasticity and heterogeneity in the development and progression of IPF, effects of drug treatment on transcriptional changes. Finally, we provide a brief outlook on future challenges and promises for large scale sequencing studies in the development of novel therapeutics for IPF.

Early Identification, Accurate Diagnosis, and Treatment of Silicosis

“…Single-cell RNA sequencing (scRNA-seq) provides a robust and unbiased survey of the transcriptome that is comparable to bulk RNA sequencing, while preserving cellular heterogeneity information has contributed to impressive advancements, including the discoveries of the pulmonary ionocyte and the profibrotic macrophage population in pulmonary fibrosis [ 26 ]. Emerging data from scRNA-seq analysis have provided novel insights on the dysfunction of alveolar type II progenitor epithelial cells and the diversity of mesenchymal cells within the fibrotic lung [ 27 ]. Spatial transcriptomics can extend and complement scRNA-seq studies and allow better characterization of the physiological interactions between cell types as well as their alterations in respiratory diseases, thereby providing key insights to understand their physiopathology [ 27 , 28 ].…”

DNA Methylation of Fibroblast Phenotypes and Contributions to Lung Fibrosis

“…Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease, characterized by excessive extracellular matrix deposition in the lung interstitium, destruction of the normal parenchymal structure and progressive loss of pulmonary function [50,51]. The traditional dogma states that repeated epithelial injury causes secretion of mediators that result in fibroblast proliferation and differentiation into myofibroblasts, which subsequently deposit excessive levels of ECM resulting in increased tissue stiffness.…”

“…The IPF parenchyma is probably the most well profiled by single cell expression profiling of the diseased lung states, offering a vast amount of data on the transcriptional profile of different cell types [15,21,52,53]. In IPF some focus has been on epithelial cells, as the "initiator cell", identifying sub-lineages of epithelial ATII cells, basal cells and an ECM-producing epithelial population [51]. However, of the mesenchymal cells, myofibroblasts have been a focus due to their normal role in helping form alveoli in development and restore tissue integrity after injury [51] but also their pathological role as the primary drivers of ECM deposition in fibrosis and as the IPF effector cell with fibroblast synthesizing capacity doubled with airway smooth muscle line contractile characteristics.…”

“…In IPF some focus has been on epithelial cells, as the "initiator cell", identifying sub-lineages of epithelial ATII cells, basal cells and an ECM-producing epithelial population [51]. However, of the mesenchymal cells, myofibroblasts have been a focus due to their normal role in helping form alveoli in development and restore tissue integrity after injury [51] but also their pathological role as the primary drivers of ECM deposition in fibrosis and as the IPF effector cell with fibroblast synthesizing capacity doubled with airway smooth muscle line contractile characteristics. The most recent single cell fibroblast study by Liu et al [16] was a comprehensive study using both new and previously published data to try to standardize the definition of fibroblasts subtypes.…”

Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis

“…Past studies have profiled gene expression in lung tissues, peripheral blood and isolated cells through microarray and bulk/single cell RNA-sequencing analyses, identifying aberrant cell populations as well as molecular signatures of progressive IPF [ 7 – 12 ]. Recent IPF biomarker efforts have focused on identification of circulating biomarkers using plasma/serum or secreted biomarkers in matrices such as Broncho alveolar lavage, sputum and breath condensate obtained through minimally invasive procedures [ 13 – 15 ].…”