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Mucous cell metaplasia is a hallmark of airway diseases, such as asthma and chronic obstructive pulmonary disease. The majority of human airway epithelium is pseudostratified, but the cell of origin of mucous cells has not been definitively established in this type of airwayepithelium.Thereisevidencethatciliated,clubcell(Clara),and basal cells can all give rise to mucus-producing cells in different contexts. Becausepseudostratified airwayepithelium containsdistinct progenitor cells from simple columnar airway epithelium, the lineage relationships of progenitor cells to mucous cells may be different in these two epithelial types. We therefore performed lineage tracing of the ciliated cells of the murine basal cell-containing airway epi- thelium in conjunction with the ovalbumin (OVA)-induced murine model of allergic lung disease. We genetically labeled ciliated cells with enhanced Yellow Fluorescent Protein (eYFP) before the aller- gen challenge, and followed the fate of these cells to determine whether they gave rise to newly formed mucous cells. Although cil- iated cells increased in number after the OVA challenge, the newly formed mucous cells were not labeled with the eYFP lineage tag. Even small numbers of labeled mucous cells could not be detected, implying that ciliated cells make virtually no contribution to the new goblet cell pool. This demonstrates that, after OVA challenge, new mucouscellsdo notoriginate from ciliated cellsin a pseudostratified basal cell-containing airway epithelium.
Keywords: mucous cell metaplasia; pseudostratified airway epithelium; ovalbumin; ciliated cell; goblet or mucous cell
Mucous metaplasia is one of hallmarks of respiratory diseases, such as asthma (1) and chronic obstructive pulmonary disease (COPD) (2). It is characterized by an increased number of mu- cous cells (goblet cells) in the airway epithelium and, conse- quently, an excess of airway mucus that can contribute to airway obstruction, mucus plugging, chronic cough, decreased pulmo- nary function, increased risk of infection, and death (3-7). Mouse models of the acute allergic response to inhaled allergens, such as ovalbumin (OVA), are frequently used to study features of clinical asthma, including the appearance of goblet cells (8-10). Mechanistically, IL-13 is known to promote goblet cell meta- plasia in murine models of allergic lung disease (11-14), and in- creased levels of IL-13 are associated with asthma and COPD (3,15,16). Recently, SAM pointed domain containing ets tran- scription factor (SPDEF) and Forkhead box protein A3 (FOXA3) have been identified as transcription...