Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population

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 ILD (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.

MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway

“…The senescence phenotype of ATII and the lung fibroblast are also abundant in the lungs of IPF patients [ 67 ]. Recent studies have reported that MUC16 expression correlates with the expression of the senescence marker p16 in IPF lung tissue [ 68 ]. Therefore, we speculate that MUC16 may also collaborate with TGF-β1 to induce cell senescence.…”

High CXCL6 drives matrix expression and correlate with markers of poor outcome in IPF

“…To further corroborate the localization of CXCL5/6 expression in IPF lungs, we also queried our recently published IPF scRNASeq dataset (Figure 3A) (15). CXCL6 was expressed predominately in goblet cells, ciliated cells, basal cells, club cells, type I cells, and fibroblasts (16). For comparison, we also analyzed CXCL5 gene expression by scRNASeq and found that CXCL5 is expressed in inflammatory cells including macrophages (Figure 3B).…”

From pulmonary fibrosis to progressive pulmonary fibrosis: a lethal pathobiological jump

“…Immunostaining for senescent markers p16 and p21 have been localized to AEC2 in patients with IPF and non-IPF UIP (44). In a recent study performed in IPF and SSc-ILD lung tissues, p16 was predominantly localized to bronchiolized epithelium lining honeycomb cysts, specifically to KRT17 + basal epithelial cells that also coexpress KRT5 + (14). This finding is different from the reported by other authors (2,27,63), which found senescence markers in KRT5 -/KRT17 + epithelial cells, supporting the difficulty to identify with precision the senescent epithelial cells in fibrotic lungs.…”