Abstract
Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to characterize context-specific cellular senescence in human lung are lacking. We observed that the senescent marker p16 is predominantly localized to bronchiolized epithelial structures in scarred regions of IPF and systemic sclerosis–associated interstitial lung disease (SSc-ILD) lung tissue, overlapping with the basal epithelial markers Keratin 5 and Keratin 17. Using in vitro models, we derived transcriptional signatures of senescence programming specific to different types of lung epithelial cells and interrogated these signatures in a single-cell RNA-Seq data set derived from control, IPF, and SSc-ILD lung tissue. We identified a population of basal epithelial cells defined by, and enriched for, markers of cellular senescence and identified candidate markers specific to senescent basal epithelial cells in ILD that can enable future functional studies. Notably, gene expression of these cells significantly overlaps with terminally differentiating cells in stratified epithelia, where it is driven by p53 activation as part of the senescence program.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease wherein the distal lung tissue is mired in a perpetual wound response due, in part, to defective alveolar epithelial repair [1, 2]
We evaluated the cellular senescence marker p16 (CDKN2A), through gene expression and protein localization in the context of control, IPF, and sclerosis–associated interstitial lung disease (SSc-Interstitial lung disease (ILD)) lung tissue
We replicated these findings in a separate cohort of patients using bulk RNA-Seq and observed a significant induction in CDKN2A gene expression in both IPF and SSc-ILD samples compared with controls (Figure 1B)
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic lung disease wherein the distal lung tissue is mired in a perpetual wound response due, in part, to defective alveolar epithelial repair [1, 2]. ILD, on the whole, is heterogeneous, which is reflected in the highly variable course of disease progression, and while it is well established that fibrosis in IPF and SSc-ILD is characterized by activity of myofibroblast-activating pathways such as TGF signaling, the events that lie upstream of and precipitate these pathways are not well characterized. Genetic studies have implicated multiple genes whose dysfunction may serve to potentiate the development of pulmonary fibrosis, which have provided insight into factors proximal to initiating/early events [9, 10]
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