title: Characterization of oncocytes in deep esophageal glands.
abstract: Deep esophageal glands play a vital role in the protection and regeneration of the esophageal mucosa. Conditions such as gastroesophageal reflux disease and Barrett's esophagus have been associated with a change in the usual glands by oncocytic metaplasia. However, little is known regarding the function of oncocytes or the relevance of this metaplastic change in the human esophagus. We hypothesized that oncocytes of deep esophageal glands also express markers characteristic of a ductal epithelial phenotype because similar oncocytes have been described as part of large ductal epithelial cells in salivary glands. We used immunohistochemical stains to define structural, functional, proliferative, and potential stem/progenitor characteristics of oncocytes. Oncocytes did not express mucins or lysozyme C, two molecules found in mucous cells and used for antimicrobial defense. Oncocytes did not express CK5, a cytokeratin found in myoepithelial cells and basal epithelial cells, but expressed CK7, a cytokeratin found in intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Oncocytes expressed cystic fibrosis transmembrane conductance regulator and sodium/potassium ATPase, ion channels that play a role in bicarbonate secretion. Membrane-bound beta-catenin was detected in oncocytes, but these cells did not express the proliferative marker Ki67. Approximately, a third of oncocytes expressed SOX9 and p63, transcription factors expressed in epithelial progenitor cells in multiple organs. Moreover, oncocytes expressed CD44, a transmembrane Glycoprotein expressed in cancer stem cells. Taken together, our data show that oncocytes express markers of intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Additionally, our observations suggest that oncocytes act as epithelial progenitor cells and play a role in bicarbonate secretion. Since oncocytic metaplasia is associated with conditions of chronic acid injury, it is possible that oncocytes replace the mucous cells in deep esophageal glands (dEG) as an adaptive change to counteract injury from acid reflux. The marker characterization suggests that oncocytes may originate from transdifferentiation of myoepithelial and mucous cells. This transdifferentiation might lead to an overall decrease of mucins production and secretion by the dEG and a subsequent reduction of the protection conferred by the viscoelastic mucous layer.
authors.affiliation: Department of Research, Veterans Affairs Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: G
authors.identifier: http://orcid.org/0000-0003-1842-3119
authors.initials: G
authors.lastname: Gonzalez
authors.affiliation: Department of Research, Veterans Affairs Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Research, Veterans Affairs Boston Healthcare System and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mashimo
mesh_terms: D054338:Cell Transdifferentiation; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D004947:Esophagus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007150:Immunohistochemistry; D053555:Keratin-5 / Q000378:metabolism; D053552:Keratin-7 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008679:Metaplasia; D009077:Mucins / Q000378:metabolism; D009113:Muramidase / Q000378:metabolism; D024862:Oxyphil Cells / Q000166:cytology / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D018960:Hyaluronan Receptors; D053555:Keratin-5; D053552:Keratin-7; D019394:Ki-67 Antigen; D009077:Mucins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009113:Muramidase; C514728:lysozyme C, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: biomarker; cellular biology; esophagus; histopathology; immunohistochemistry