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EGF Shifts Human Airway Basal Cell Fate Toward a Smoking-Associated Airway Epithelial Phenotype

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EGF Shifts Human Airway Basal Cell Fate Toward a Smoking-Associated Airway Epithelial Phenotype EGF shifts human airway basal cell fate toward a smoking-associated airway epithelial phenotype Renat Shaykhiev1, Wu-Lin Zuo1, IonWa Chao, Tomoya Fukui, Bradley Witover, Angelika Brekman, and Ronald G. Crystal2 Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065 Edited* by Michael J. Welsh, Howard Hughes Medical Institute, Iowa City, IA, and approved May 29, 2013 (received for review February 19, 2013) The airway epithelium of smokers acquires pathological phenotypes, phosphorylation, indicative of EGFR receptor activation, has including basal cell (BC) and/or goblet cell hyperplasia, squamous been observed in airway epithelial cells exposed to cigarette metaplasia, structural and functional abnormalities of ciliated cells, smoke in vitro (26, 27). decreased number of secretoglobin (SCGB1A1)-expressing secretory Based on this knowledge, we hypothesized that smoking- cells, and a disordered junctional barrier. In this study, we hypoth- induced changes in the EGFR pathway are relevant to the EGFR- fi esized that smoking alters airway epithelial structure through dependent modi cation of BCs toward the abnormal differentia- modification of BC function via an EGF receptor (EGFR)-mediated tion phenotypes present in the airway epithelium of smokers. mechanism. Analysis of the airway epithelium revealed that EGFR is In this study, we provide evidence that although EGFR is ex- pressed predominantly in BCs, smoking induces expression of enriched in airway BCs, whereas its ligand EGF is induced by smoking EGF in ciliated cells of the airway epithelium, and activation of in ciliated cells. Exposure of BCs to EGF shifted the BC differentiation – airway BCs with EGF skews their differentiation from the nor- program toward the squamous and epithelial mesenchymal transi- mal mucociliary pathway toward the squamous and epithelial– tion-like phenotypes with down-regulation of genes related to cilio- mesenchymal transition (EMT)-like phenotypes with decreased genesis, secretory differentiation, and markedly reduced junctional epithelial junctional barrier integrity. barrier integrity, mimicking the abnormalities present in the airways of smokers in vivo. These data suggest that activation of EGFR in Results airway BCs by smoking-induced EGF represents a unique mechanism Enrichment of EGFR Gene Expression in Airway Basal Cells. Signaling PHYSIOLOGY whereby smoking can alter airway epithelial differentiation and through various ErbB family receptors in polarized epithelia, barrier function. including that in the airways, is determined, at least in part, by segregated distribution of the receptors and their ligands in ei- airway epithelial barrier | progenitor cell | cigarette smoking ther apical or basolateral membrane domains (28, 29). We hy- pothesized that an additional compartmentalization could be he normally differentiated human airway epithelium is a provided by the heterogeneous expression of the ErbB family Tpseudostratified layer composed of apically positioned dif- receptors and their ligands between the BC and BC-derived ferentiated ciliated and secretory cells, intermediate columnar differentiated cell populations, such as ciliated and secretory cells, and basal cells (BCs) located just above the basement cells, contributing to the luminal compartment. Microarray-based membrane (1, 2). BCs are the stem/progenitor cells for the air- gene expression analysis of the complete large airway epithelium way epithelium. Normal BC function includes generation of air- (LAE) compared with the LAE-derived BCs from healthy non- way basal, secretory, and ciliated cells (3–5). Cigarette smoking is smokers revealed compartmentalized expression of the EGFR associated with dramatic changes in the airway epithelial archi- family receptors in the normal human airway epithelium in vivo A tecture, inducing BC hyperplasia, mucus overproduction, and (Fig. 1 ). fi squamous metaplasia (6, 7). Squamous metaplasia represents Consistent with previous immunohistochemistry ndings (20, a histological lesion characterized by conversion to a stratified 22, 29), EGFR gene expression was much greater compared with A epithelium comprised of flattened squamous cells replacing the other ErbB receptors and was enriched in BCs (Fig. 1 ). In differentiated cell populations (6, 7). Other smoking-induced contrast, expression of ERBB4 was barely detectable in BCs, but fi changes include structural and functional abnormalities of ciliated was signi cantly greater in differentiated airway epithelium (Fig. A cells (8, 9), disorganization of cell–cell junctions leading to in- 1 ). These differences were related to cell differentiation status creased permeability of the airway epithelial barrier (10–12), and and not to the culture itself, given that expression of neither fi decreased numbers of secretoglobin (SCGB) 1A1-expressing se- EGFR nor ERBB4 varied signi cantly during the expansion A cretory cells (13). Persistence of these changes in the context of phase, when BCs were grown as submerged cultures (Fig. S1 B chronic cigarette smoking is associated with decreased mucociliary and ). However, EGFR gene expression was dramatically de- creased and ERBB4 expression was markedly increased during clearance, pathogen colonization, and development of smoking- – associated lung disorders, chronic obstructive pulmonary disease, the BC differentiation phase in the air liquid interface (ALI) – model, recapitulating the expression pattern observed in the and lung cancer (6, 7, 14 16). A–C Altered BC function might be one possible mechanism of airway epithelium in vivo (Fig. S1 ). Enrichment of EGFR expression in the BC population was smoking-induced dysregulation of airway epithelial differentia- fi tion. Consistent with this concept are the observations of in- further con rmed through immunohistochemistry analysis of creased numbers of BCs in the airways of smokers (6, 7), overexpression of BC markers keratin (KRT) 5, KRT14, and tumor protein (TP) 63 in squamous lesions (6, 17), and the Author contributions: R.S., W.-L.Z., and R.G.C. designed research; R.S., W.-L.Z., I.C., T.F., ability of BCs to form squamous epithelium in vitro (18). A B.W., and A.B. performed research; R.G.C. contributed new reagents/analytic tools; R.S., molecular mechanism contributing to smoking-induced changes W.-L.Z., and R.G.C. analyzed data; and R.S. and R.G.C. wrote the paper. in BC function could be activation of EGF receptor (EGFR), The authors declare no conflict of interest. a member of the ErbB (v-erb-b oncogene homolog) family of *This Direct Submission article had a prearranged editor. tyrosine kinase receptors (19). EGFR is enriched in cells of the 1R.S. and W.-L.Z. contributed equally to this work. basal layer of various epithelial tissues, including the airways 2To whom correspondence should be addressed. E-mail: [email protected]. (20–22), and has been implicated in regulation of epithelial ho- edu. meostasis and tissue repair, production of host defense media- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tors, and production of mucin (23–25). Increased EGFR tyrosine 1073/pnas.1303058110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1303058110 PNAS Early Edition | 1of6 Downloaded by guest on October 2, 2021 Basal cells A 150 * Basal cells C Complete airway KRT5 epithelium EGFR 100 N.S. N.S. 50 * Normalized expression 0 D Basal ALI (days) EGFR ERBB2 ERBB3 ERBB4 cells 8 28 28 Fig. 1. Enrichment of EGFR in airway BCs. (A) Nor- B malized expression of the ErbB family receptors in the Airway epithelium in vivo Airway brushes EGFR complete differentiated LAE of healthy nonsmokers = GAPDH (n 21) and LAE-derived BCs of healthy nonsmokers (n = 4) based on the microarray analysis. N.S., not significant. *P < 0.05. (B) Localization of EGFR in the human airway epithelium. (Left) EGFR immunohisto- E chemistry of the LAE biopsy samples. (Right, Top)EGFR ALI d28 immunocytochemistry of an airway epithelial brushing KRT5 KRT5 sample. (Right, Middle and Bottom) Immunofluores- EGFR EGFR cence colocalization of EGFR and KRT5 in the airway epithelial brushings. (C) Representative immunofluo- rescence image of BCs cultured from the LAE stained for EGFR and KRT5. (D) Western blot analysis of EGFR protein expression in airway BCs at baseline and in BC- Apical side KRT5 KRT5 derived airway epithelium generated from BCs after EGFR EGFR 8 d and 28 d of culture in ALI. GAPDH expression is shown as a loading control. (E) Immunofluorescence analysis of cytopreparations of airway epithelial cells generated from BCs after 28 d of culture in ALI dou- ble-stained for EGFR and KRT5; two representative images are shown. (Scale bars: 20 μm.) LAE biopsy specimens and freshly isolated LAE brushed cells To determine whether cigarette smoke can directly induce (Fig. 1B). Immunofluorescence analysis of the airway epithelial EGF in the differentiated airway epithelium, we applied ciga- brushings obtained from different donors (Fig. 1B and Fig. S2A) rette smoke extract (CSE) to the differentiated airway epithe- revealed that >80% of EGFR-expressing cells were positive for lium generated from BCs in ALI culture. For modeling of BC marker keratin KRT5, and that >70% of BCs expressed repeated prolonged smoking exposure, CSE was added from the EGFR (Fig. S2B). The latter finding points toward heterogeneity apical side for 24 h every other day over a 2-wk period. Signifi- of BCs in terms of EGFR protein expression. This heteroge- cant up-regulation of EGF gene expression
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