PMID- 31557955 OWN - NLM STAT- MEDLINE DCOM- 20200615 LR - 20200615 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 8 IP - 10 DP - 2019 Sep 25 TI - Mesenchymal WNT-5A/5B Signaling Represses Lung Alveolar Epithelial Progenitors. LID - 10.3390/cells8101147 [doi] LID - 1147 AB - 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. FAU - Wu, Xinhui AU - Wu X AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. x.wu@rug.nl. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. x.wu@rug.nl. FAU - van Dijk, Eline M AU - van Dijk EM AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. aanelien@gmail.com. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. aanelien@gmail.com. FAU - Ng-Blichfeldt, John-Poul AU - Ng-Blichfeldt JP AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. jpblich@mrc-lmb.cam.ac.uk. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. jpblich@mrc-lmb.cam.ac.uk. FAU - Bos, I Sophie T AU - Bos IST AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. I.S.T.Bos@rug.nl. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. I.S.T.Bos@rug.nl. FAU - Ciminieri, Chiara AU - Ciminieri C AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. c.ciminieri@rug.nl. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. c.ciminieri@rug.nl. AD - Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, CO 80045 Aurora, USA. c.ciminieri@rug.nl. FAU - Konigshoff, Melanie AU - Konigshoff M AD - Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, CO 80045 Aurora, USA. melanie.koenigshoff@ucdenver.edu. FAU - Kistemaker, Loes E M AU - Kistemaker LEM AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. l.e.m.kistemaker@rug.nl. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. l.e.m.kistemaker@rug.nl. AD - Aquilo BV, 9713 AV Groningen, The Netherlands. l.e.m.kistemaker@rug.nl. FAU - Gosens, Reinoud AU - Gosens R AD - Department of Molecular Pharmacology, Faculty of Science and Engineering, University of Groningen, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands. r.gosens@rug.nl. AD - Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. r.gosens@rug.nl. LA - eng GR - R01 HL141380/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190925 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Wnt Proteins) RN - 0 (Wnt-5a Protein) RN - 0 (Wnt5a protein, mouse) RN - 0 (Wnt5b protein, mouse) SB - IM MH - Aging/*metabolism MH - Alveolar Epithelial Cells/*cytology/metabolism MH - Animals MH - Cell Differentiation MH - Cell Line MH - Cell Proliferation MH - Coculture Techniques MH - Female MH - Fibroblasts/cytology MH - Humans MH - Male MH - Mice MH - Organoids/*cytology/metabolism MH - Pulmonary Disease, Chronic Obstructive/*metabolism MH - Stem Cells/cytology/metabolism MH - Up-Regulation MH - Wnt Proteins/*metabolism MH - Wnt Signaling Pathway MH - Wnt-5a Protein/*metabolism PMC - PMC6829372 OTO - NOTNLM OT - WNT signaling pathway OT - WNT-5A OT - WNT-5B OT - alveolar repair OT - chronic obstructive pulmonary disease (COPD) OT - lung organoids OT - precision-cut-lung slices (PCLS) COIS- The authors declare no conflict of interest. EDAT- 2019/09/29 06:00 MHDA- 2020/06/17 06:00 PMCR- 2019/10/01 CRDT- 2019/09/28 06:00 PHST- 2019/08/29 00:00 [received] PHST- 2019/09/17 00:00 [revised] PHST- 2019/09/25 00:00 [accepted] PHST- 2019/09/28 06:00 [entrez] PHST- 2019/09/29 06:00 [pubmed] PHST- 2020/06/17 06:00 [medline] PHST- 2019/10/01 00:00 [pmc-release] AID - cells8101147 [pii] AID - cells-08-01147 [pii] AID - 10.3390/cells8101147 [doi] PST - epublish SO - Cells. 2019 Sep 25;8(10):1147. doi: 10.3390/cells8101147.