Dysregulation of club cell biology in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. “Bronchiolization”, characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1 + club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1 + MUC5B + club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1 + SCGB3A2 high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.

Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

“… 32 Abnormal distribution of club cells has been reported in IPF lungs. 7 8 22 Interestingly, recent single-cell RNA seq and RNA in situ hybridisation studies also indicated the increases in club cell signature in the parenchyma of the patients with IPF. 8 33 A recent study also suggested that progenitor SCGB1A1 niches are present in the alveolar regions and act as reservoirs for alveolar type II (ATII) epithelial cells during the injury and repair process of the lung.…”

“… 3 4 There is increasing evidence that club cells play essential roles in lung repair and found in the distal lung in IPF. 5 – 8 However, the role of these distal club cells in lung fibrosis is not well studied.…”

Cigarette Smoke Specifically Affects Small Airway Epithelial Cell Populations and Triggers the Expansion of Inflammatory and Squamous Differentiation Associated Basal Cells

“…Beyond the known mucous secretory cell (SC3) subset [ 33 ], this study resolved a SCGB3A2 + secretory cell cluster (SC4) with low mucin-related gene expression that has recently been observed in human lung specimens. However, these studies were not able to explicitly demonstrate its presence in the small airways [ 61 , 62 ]. Diversity in the secretory cell fraction was further demonstrated by variable expression of MHC-II components.…”

BSDE: barycenter single-cell differential expression for case–control studies

“…In light of these findings, we review previous results from the literature on the identified cell types and DEGs related to PF; see Table 1 and Table S1 ( Supplementary Materials ). In particular, DEG-enriched cell types SCGB3A2 ( Cai and Kimura, 2015 ; Zuo et al , 2020 ), AT2 ( Parimon et al , 2020 ; Wu et al , 2020 ), MUC5B ( Peljto et al , 2013 ; Seibold et al , 2011 ; Zuo et al , 2020 ) and Basal ( Carraro et al , 2020 ; Richeldi et al , 2017 ) have been previously reported.…”