14 research outputs found
Sa1161 – Late Recurrence of Dysplastic Barrett's Esophagus and Esophageal Adenocarcinoma After Endoscopic Eradication Therapy
Sa1163 - Lamina Propria Fibrosis and Eosinophil Count do not Correlate with Esophageal Distensibility in Eosinophilic Esophagitis
Sa1156 – Participation in Non-Endoscopic Screening Techniques for Barrett's Esophagus: A Prospective Multicenter Study
Su1178 Matrix-Stiffness Enhances Esophageal Fibroblast Activation, Proliferation and Contractility in Pediatric and Adult Fibroblasts
169 – Interleukin-13-Mediated Release of Mitochondrial Dna from Esophageal Epithelial Cells: A Novel Biomarker for Eosinophilic Esophagitis
526 Autophagy Is an Epithelial Cytoprotective Mechanism in Esophageal Epithelial Cells in Response to Eosinophilic Esophagitis-Associated Inflammation
204 Epithelial Lysyl Oxidase Is an Early Mediator of Fibrotic Remodeling in Eosinophilic Esophagitis
460 - Inflammatory Cytokines Diminish Notch Signaling to Drive Reactive Epithelial Changes in Eosinophilic Esophagitis
The Esophageal Organoid System Reveals Functional Interplay Between Notch and Cytokines in Reactive Epithelial Changes
Aberrations in the esophageal proliferation-differentiation gradient are histologic hallmarks in eosinophilic esophagitis (EoE) and gastroesophageal reflux disease. A reliable protocol to grow 3-dimensional (3D) esophageal organoids is needed to study esophageal epithelial homeostasis under physiological and pathologic conditions.
Methods: We modified keratinocyte-serum free medium to grow 3D organoids from endoscopic esophageal biopsies, immortalized human esophageal epithelial cells, and murine esophagi. Morphologic and functional characterization of 3D organoids was performed following genetic and pharmacologic modifications or exposure to EoE-relevant cytokines. The Notch pathway was evaluated by transfection assays and by gene expression analyses in vitro and in biopsies.
Results: Both murine and human esophageal 3D organoids displayed an explicit proliferation-differentiation gradient. Notch inhibition accumulated undifferentiated basal keratinocytes with deregulated squamous cell differentiation in organoids. EoE patient-derived 3D organoids displayed normal epithelial structure ex vivo in the absence of the EoE inflammatory milieu. Stimulation of esophageal 3D organoids with EoE-relevant cytokines resulted in a phenocopy of Notch inhibition in organoid 3D structures with recapitulation of reactive epithelial changes in EoE biopsies, where Notch3 expression was significantly decreased in EoE compared with control subjects.
Conclusions: Esophageal 3D organoids serve as a novel platform to investigate regulatory mechanisms in squamous epithelial homeostasis in the context of EoE and other diseases. Notch-mediated squamous cell differentiation is suppressed by cytokines known to be involved in EoE, suggesting that this may contribute to epithelial phenotypes associated with disease. Genetic and pharmacologic manipulations establish proof of concept for the utility of organoids for future studies and personalized medicine in EoE and other esophageal diseases