CiliOPD: a ciliopathy-associated COPD endotype

Abstract

The pathophysiology of chronic obstructive pulmonary disease (COPD) relies on airway remodelling and inflammation. Alterations of mucociliary clearance are a major hallmark of COPD caused by structural and functional cilia abnormalities. Using transcriptomic databases of whole lung tissues and isolated small airway epithelial cells (SAEC), we comparatively analysed cilia-associated and ciliopathy-associated gene signatures from a set of 495 genes in 7 datasets including 538 non-COPD and 508 COPD patients. This bio-informatics approach unveils yet undescribed cilia and ciliopathy genes associated with COPD including NEK6 and PROM2 that may contribute to the pathology, and suggests a COPD endotype exhibiting ciliopathy features (CiliOPD).

Primary ciliogenesis is a crucial step for multiciliated cell determinism in the respiratory epithelium

“…We recently demonstrated the presence of PC in human airway epithelial undifferentiated cells during homeostasis and in chronic obstructive pulmonary disease (COPD) 2 . In addition, recent studies reported a decrease in multiciliated cells (MCC) in COPD patient‐derived bronchial and bronchiolar air‐liquid interface (ALI) cultures, 3,4 and we highlighted an abnormal cilia‐associated genomic signature in COPD patients (CiliOPD 5 ). As it was suggested that multiciliated cells (MCC) originated from primary ciliated cells (PCC), 6 we investigated the consequences of PC removal on human airway epithelial cell (AEC) differentiation.…”

“…airway epithelium, cell differentiation, cilia genomic signature in COPD patients (CiliOPD 5 ). As it was suggested that multiciliated cells (MCC) originated from primary ciliated cells (PCC), 6 we investigated the consequences of PC removal on human airway epithelial cell (AEC) differentiation.…”

Comparative transcriptomics in human COPD reveals dysregulated genes uniquely expressed in ferrets

“…Common DEGs between ferret, human, and mouse also reinforced the contribution of additional genes to COPD pathogenesis. Among other overlapping DEGs, TREM2 has been observed to promote macrophage survival in the lung [ 47 ], nimA-related protein kinase 6 (NEK6) has been implicated in COPD-associated ciliopathies [ 48 ], and cathepsin B (CTSB) induced emphysema and secretory cell hyperplasia upon intratracheal administration to hamster lungs [ 49 ]. Additional genes of interest that were substantially upregulated and have direct relevance to COPD and/or cigarette smoke exposure included SERPINA1 (2.17 log 2 fold change (log 2 FC); p adj = 5.13E−26), ATP6V0D2 (3.99 log 2 FC; p adj = 3.42E−26), MMP-12 (2.69 log 2 FC ; p adj = 6.20E−12), AHRR (1.74 log 2 FC; p adj = 8.32E−05), and CTSB (1.83 log 2 FC; p adj = 4.64E−18), among others [ 4 , 50 ].…”

Whole-Exome Sequencing of Bronchial Epithelial Cells Reveals a Genetic Print of Airway Remodelling in COPD

“…The functional analysis of our guided approach pointed to a genetic alteration of the cilia that may extend further than what were already identified as cilia regulators. Since COPD exome and transcriptome sequencing often incriminated cilia-associated genes [ 1 , 3 , 14 , 15 ], the identification, the molecular characterization and the clinical validation of these key actors appeared to be highly significant in respiratory research. Additionally, we unveiled the genetic alterations of two hits that were previously suggested as a useful biomarker of smokers at risk of developing COPD (COL14A1, [ 16 ]) and emphysema-associated regulator (AMOTL1, [ 17 ]).…”