Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
Eline M. van Dijk
Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
John-Poul Ng-Blichfeldt
Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
I. Sophie T. Bos
Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
Chiara Ciminieri
Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
Melanie Königshoff
Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USA
Loes E.M. Kistemaker
Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
Reinoud Gosens
Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands
Chronic obstructive pulmonary disease (COPD) represents a worldwide concern with high morbidity and mortality, and is believed to be associated with accelerated ageing of the lung. Alveolar abnormalities leading to emphysema are a key characteristic of COPD. Pulmonary alveolar epithelial type 2 cells (AT2) produce surfactant and function as progenitors for type 1 cells. Increasing evidence shows elevated WNT-5A/B expression in ageing and in COPD that may contribute to the disease process. However, supportive roles for WNT-5A/B in lung regeneration were also reported in different studies. Thus, we explored the role of WNT-5A/B on alveolar epithelial progenitors (AEPs) in more detail. We established a Precision-Cut-Lung Slices (PCLS) model and a lung organoid model by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with fibroblasts in matrigel in vitro to study the impact of WNT-5A and WNT-5B. Our results show that WNT-5A and WNT-5B repress the growth of epithelial progenitors with WNT-5B preferentially restraining the growth and differentiation of alveolar epithelial progenitors. We provide evidence that both WNT-5A and WNT-5B negatively regulate the canonical WNT signaling pathway in alveolar epithelium. Taken together, these findings reveal the functional impact of WNT-5A/5B signaling on alveolar epithelial progenitors in the lung, which may contribute to defective alveolar repair in COPD.
