Ductular and proliferative response of esophageal submucosal glands in a porcine model of esophageal injury and repair

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2017-09, Vol.313 (3), p.G180-G191
• Main Authors: Krüger, Leandi, Gonzalez, Liara M, Pridgen, Tiffany A, McCall, Shannon J, von Furstenberg, Richard J, Harnden, Ivan, Carnighan, Gwendolyn E, Cox, Abigail M, Blikslager, Anthony T, Garman, Katherine S
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus; Adenocarcinoma; Animal models; Animals; Barrett's esophagus; Cell Proliferation - physiology; Epithelium; Esophageal Diseases - pathology; Esophagus; Esophagus - cytology; Esophagus - injuries; Female; Gene Expression Regulation - physiology; Glands; Humans; Male; Medical treatment; Metaplasia; Mucosa; Pathogenesis; Risk factors; Sox9 protein; SOX9 Transcription Factor - genetics; SOX9 Transcription Factor - metabolism; Staining and Labeling; Swine
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00036.2017

Esophageal injury is a risk factor for diseases such as Barrett's esophagus (BE) and esophageal adenocarcinoma. To improve understanding of signaling pathways associated with both normal and abnormal repair, animal models are needed. Traditional rodent models of esophageal repair are limited by the absence of esophageal submucosal glands (ESMGs), which are present in the human esophagus. Previously, we identified acinar ductal metaplasia in human ESMGs in association with both esophageal injury and cancer. In addition, the SOX9 transcription factor has been associated with generation of columnar epithelium and the pathogenesis of BE and is present in ESMGs. To test our hypothesis that ESMGs activate after esophageal injury with an increase in proliferation, generation of a ductal phenotype, and expression of SOX9, we developed a porcine model of esophageal injury and repair using radiofrequency ablation (RFA). The porcine esophagus contains ESMGs, and RFA produces a consistent and reproducible mucosal injury in the esophagus. Here we present a temporal assessment of this model of esophageal repair. Porcine esophagus was evaluated at 0, 6, 18, 24, 48, and 72 h and 5 and 7 days following RFA and compared with control uninjured esophagus. Following RFA, ESMGs demonstrated an increase in ductal phenotype, echoing our prior studies in humans. Proliferation increased in both squamous epithelium and ESMGs postinjury with a prominent population of SOX9-positive cells in ESMGs postinjury. This model promises to be useful in future experiments evaluating mechanisms of esophageal repair. A novel porcine model of injury and repair using radiofrequency ablation has been developed, allowing for reproducible injury to the esophagus to study repair in an animal model with esophageal submucosal glands, a key anatomical feature and missing in rodent models but possibly harboring progenitor cells. There is a strong translational component to this porcine model given the anatomical and physiological similarities between pigs and humans.