Retinoic acid signaling balances adult distal lung epithelial progenitor cell growth and differentiationResearch in context
John-Poul Ng-Blichfeldt,
Anneke Schrik,
Rosa K. Kortekaas,
Jacobien A. Noordhoek,
Irene H. Heijink,
Pieter S. Hiemstra,
Jan Stolk,
Melanie Königshoff,
Reinoud Gosens
Affiliations
John-Poul Ng-Blichfeldt
Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands; Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the German Center of Lung Research (DZL), Munich 81377, Germany; Corresponding authors at: Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands.
Anneke Schrik
Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands
Rosa K. Kortekaas
Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands
Jacobien A. Noordhoek
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology and Pulmonology, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, 9713GZ, The Netherlands
Irene H. Heijink
University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology and Pulmonology, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, 9713GZ, The Netherlands
Pieter S. Hiemstra
Department of Pulmonology, Leiden University Medical Center, Leiden 2333ZA, The Netherlands
Jan Stolk
Department of Pulmonology, Leiden University Medical Center, Leiden 2333ZA, The Netherlands
Melanie Königshoff
Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the German Center of Lung Research (DZL), Munich 81377, Germany; Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Aurora, CO 80045, USA.
Reinoud Gosens
Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands; Corresponding authors at: Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands.
Background: Despite compelling data describing pro-regenerative effects of all-trans retinoic acid (ATRA) in pre-clinical models of chronic obstructive pulmonary disease (COPD), clinical trials using retinoids for emphysema patients have failed. Crucial information about the specific role of RA signaling in adult rodent and human lung epithelial progenitor cells is largely missing. Methods: Adult lung organoid cultures were generated from isolated primary mouse and human lung epithelial cells, and incubated with pharmacological pathway modulators and recombinant proteins. Organoid number and size were measured, and differentiation was assessed with quantitative immunofluorescence and gene expression analyses. Findings: We unexpectedly found that ATRA decreased lung organoid size, whereas RA pathway inhibition increased mouse and human lung organoid size. RA pathway inhibition stimulated mouse lung epithelial proliferation via YAP pathway activation and epithelial-mesenchymal FGF signaling, while concomitantly suppressing alveolar and airway differentiation. HDAC inhibition rescued differentiation in growth-augmented lung organoids. Interpretation: In contrast to prevailing notions, our study suggests that regenerative pharmacology using transient RA pathway inhibition followed by HDAC inhibition might hold promise to promote lung epithelial regeneration in diseased adult lung tissue. Fund: This project is funded by the Lung Foundation Netherlands (Longfonds) grant 6.1.14.009 (RG, MK, JS, PSH) and W2/W3 Professorship Award by the Helmholtz Association, Berlin, Germany (MK). Keywords: Lung repair/regeneration, Adult stem cells, COPD/emphysema, Lung epithelial organoids, Retinoic acid
