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University of Groningen Developmental and Pathological Roles of BMP/Follistatin-Like 1 in the Lung Tania, Navessa

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University of Groningen Developmental and Pathological Roles of BMP/Follistatin-Like 1 in the Lung Tania, Navessa University of Groningen Developmental and pathological roles of BMP/follistatin-like 1 in the lung Tania, Navessa IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Tania, N. (2017). Developmental and pathological roles of BMP/follistatin-like 1 in the lung. University of Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 01-10-2021 CHAPTER 7 1 Variant club cell differentiation is driven by bone morphogenetic protein 4 in adult human airway epithelium: Implications for goblet cell metaplasia and basal cell hyperplasia in COPD Navessa P. Tania, Harm Maarsingh, Frank Ensink, John-Poul Ng-Blichfeldt, Pieter S. Hiemstra, Maurice J.B. van den Hoff, Martina Schmidt, Reinoud Gosens 121 Variant club cell differentiation is driven by bone morphogenetic protein 4 in adult human airway epithelium: Implications for goblet cell metaplasia and basal cell hyperplasia in COPD Navessa P. Tania1,2, Harm Maarsingh3, Frank Ensink1, John-Poul Ng-Blichfeldt1,2, Pieter S. 4 5 1,2 1,2 Hiemstra , Maurice J.B. van den Hoff , Martina Schmidt , Reinoud Gosens 1University of Groningen, Department of Molecular Pharmacology, Groningen, The Netherlands. 2University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, Groningen, The Netherlands. 3Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, Department of Pharmaceutical Sciences, West Palm Beach, Florida, USA. 4Dept. of Pulmonology, Leiden University Medical Centre, Leiden, The Netherlands. 5Academic Medical Center, Department of Anatomy, Embryology and Physiology, Amsterdam, The Netherlands. 122 Abstract Activation of BMP signaling in adult airway epithelium is required for appropriate regeneration after epithelial injury and plays key roles in proximal-to-distal patterning of airway epithelial differentiation with highest expression in the distal airways. COPD is associated with epithelial remodeling characterized by loss of functional club cells, increased goblet cell metaplasia and basal cell hyperplasia. Here, we studied the effects of BMP4 on adult airway epithelial differentiation, hypothesizing that BMP4 would regulate club cell differentiation, whilst suppressing goblet cell differentiation. An in vitro air-liquid interface (ALI) culture system was used to grow adult primary tracheobronchial epithelial cells (PTECs). After 14 days of air-exposure in the presence or absence of BMP4, distinct morphological changes were observed in BMP4-treated PTECs. BMP4 reduced gene expression for markers of ciliated (Tektin-1), goblet (MUC5AC), and basal (TP63) cells. Interestingly, BMP4 increased marker gene expression for distal variant club cells (UPK3A, SCGB3A, SFTPA), but not for common club cells (CYP2F1, SCGB1A1). Moreover, BMP4 induced gene expression of lung progenitor markers (NKX2.1, ITGA6). Mechanistically, BMP4 increased target genes downstream of Notch signaling (HEY1, HEY3) and TGF-β1 signaling (ID-1, SERPINE1). In conclusion, BMP4 promotes distal variant club cell differentiation and suppresses proximal differentiation of goblet and ciliated cells. Our findings provide a plausible connection between the loss of (variant) club cells and increased goblet cell metaplasia and basal cell hyperplasia on one hand and the observed reduction of BMP signaling in patients with COPD on the other hand. Reactivation of BMP signaling in distal airway epithelium may be a strategy worth pursuing to trigger differentiation and maintenance of distal variant club progenitor cells capable of airway epithelial repair. 7 123 Introduction In fetal and neonatal lung development, BMP signaling is crucial in governing proximal- to-distal epithelial cell fate.1–3 Loss of BMP signaling in the developing mouse lung leads to severe loss of distal epithelial cell types, whilst promoting the presence of proximal epithelial cell types - even in the most distal airway regions.3 In adult lung, it has been proposed that BMP signaling is involved in tissue repair and that inappropriate BMP activation might contribute to adult respiratory diseases, including asthma and COPD.2–4 Activation of BMP signaling in adult airway epithelium after epithelial injury regenerates normal epithelial architecture in a similar pattern as early lung development.5,6 The healthy epithelial lining of adult airways consists of a mixed population of mucus- producing (MUC5AC+) goblet cells, (TEKT1+) ciliated cells, (TP63+) basal cells, (SCGB1A1+/ CYP2F+) club cells, and (SCGB3A2+/UPK3A+/SFTPA+) variant club cells.7,8 Goblet cells are normally expressed in the proximal airway epithelium, whereas (variant) club cells are predominantly expressed in the distal airway epithelium. In COPD, airway epithelial cell differentiation programs are inappropriately activated with loss of functional club cells, increased goblet cell metaplasia, and basal cell hyperplasia as key pathological features of airway epithelium in the disease.9–12 Low levels of secretoglobin family 1A member 1 (SCGB1A1, also known as a club (formerly clara) cell secretory protein CC10 or CC16) in serum and bronchoalveolar lavage have been associated with the prevalence, severity and acceleration of a decline in forced expiratory volume in one 10,13–17 second (FEV1) in COPD in several studies. Goblet cell metaplasia is characterized by increased numbers of goblet cells in the proximal airways of COPD patients and by the appearance of goblet cells in more distal airway regions that normally do not express these cells.9 Importantly, our previous studies demonstrate that functional BMP4 signaling (Smad1/5/8 phosphorylation) is reduced in COPD (Chapter 3), which could explain the change in proximal-to-distal differentiation pattern. The air-liquid interface (ALI) culture system provides a valuable tool to study airway epithelial differentiation in vitro mimicking a polarized pseudostratified epithelium.18,19 In ALI culture, the expression of the BMP4 gene is markedly increased during mucociliary differentiation of adult airway epithelial cells.20 A recent study demonstrates that BMP signaling is a negative regulator of basal progenitor cell proliferation in mouse tracheal epithelium6 and BMP4 drives specification of adult bronchoalveolar stem cells in mice,21 yet little is known about the role of BMP4 in human airway epithelial cell differentiation. In addition, the underlying mechanisms by which BMP exerts its effect in airway epithelial cell fate is still unclear. In this study, we present evidence that BMP4 alters primary tracheobronchial epithelial cells (PTECs) morphology and induces variant club cell marker gene expression that is associated with high expression of distal epithelial and progenitor markers. In parallel, BMP4 suppresses ciliated, goblet, and basal cell marker gene expression. Our findings provide a plausible connection between the loss of (variant) club cells and increased goblet cell metaplasia and basal cell hyperplasia on one hand and the observed reduction of BMP signaling in patients with COPD on the other. Restoring 124 normal BMP signaling in distal airway epithelium may be a strategy worth pursuing to trigger differentiation and maintenance of distal variant club progenitor cells capable of airway epithelial repair. Materials and methods Air-liquid interface cultured primary tracheobronchial epithelial cells (ALI-PTEC)- human PTECs were isolated from anonymous healthy lung transplant donors. Lung transplant donors were selected according to Eurotransplant guidelines, including absence of tumor and primary chronic lung diseases, such as asthma and COPD, and with <20 pack years of smoking history. PTECs were expanded in submerged culture using keratinocyte serum free medium (17005-075, Invitrogen, CA, USA) supplemented with 25 µg/ml bovine pituitary extract and 0.2 ng/ml epidermal growth factor (37000- 015, Invitrogen, CA, USA). Generation of mucociliary differentiated PTEC cultures was conducted using air-liquid interface (ALI) system as previously described.22,23 Prior to cell seeding in the ALI culture system, transwell semipermeable inserts were coated for 2 h at 37 °C with a mixture of 30 µg/ml PureCol (Advanced BioMatrix, San Diego, CA, USA), 10 µg/ml human fibronectin, and 10 µg/ml BSA (Sigma Aldrich, St. Louis, MO, USA) dissolved in PBS. Passage 1-2 of PTECs were seeded on coated Transwell 12 mm
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