PT  - JOURNAL ARTICLE
AU  - Hu Yan
AU  - Chiara Ciminieri
AU  - Reinoud Gosens
AU  - Christopher Evans
AU  - Melanie Koenigshoff
TI  - LSC - 2021 - Club cell functions as a Wnt-responsive progenitor for tissue repair in COPD
AID  - 10.1183/13993003.congress-2021.PA3622
DP  - 2021 Sep 05
TA  - European Respiratory Journal
PG  - PA3622
VI  - 58
IP  - suppl 65
4099  - http://erj.ersjournals.com/content/58/suppl_65/PA3622.short
4100  - http://erj.ersjournals.com/content/58/suppl_65/PA3622.full
SO  - Eur Respir J2021 Sep 05; 58
AB  - Introduction: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide that is characterized by progressive loss of alveolar tissue. Endogenous lung stem cells and tissue repair pathways are thought be dysfunctional and their reactivation is a promising therapeutic approach for COPD. Wnt/ß-catenin signaling?is critical for?stem?cell function and is reduced in human COPD lungs. We previously demonstrated that therapeutic Wnt/ß-catenin initiated tissue repair in COPD patient-derived lung tissue ex vivo. Recently, we identified an epithelial progenitor population enriched with club cells, which were activated? by Wnt/ß-catenin signaling to?form?alveolar organoids. Thus, we hypothesize that club cells represent a novel Wnt-responsive epithelial progenitor for tissue repair in COPD.Methods: Single cell RNA sequencing (scRNA seq), organoid assay, fate tracing studies, flow cytometry, immunofluorescence, FACS sorting, porcine pancreatic elastase (PPE) induced mouse COPD model.Results: 1) Using scRNA seq, we identified club cells as the major progenitor cells in the Wnt-responsive epithelial progenitor cell population. 2) We perform fate tracing studies using a Scgb1a1Cre-ERT;Rosa-Tomato;TCF/Lef:H2B-GFP mouse line combined with lung organoid assays to demonstrate that activation of the Wnt/ß-catenin signaling using the GSK3 inhibitor CHIR9920 increased the number of alveolar organoids formed by club cells. 3) In a PPE-induced mouse COPD model, we identified an impaired organoid forming capacity of club cells, which could be restored by activation of the Wnt/ß-catenin signaling. Importantly, the alveolar organoid formation was largely increased.Conclusion: Our study reveals a novel mechanism of club cell activation by Wnt/ß-catenin signaling in COPD.FootnotesCite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA3622.This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).