Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids
<b>Background:</b> Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. <b>Methods:</b> We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize the ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-β receptor-mediated signaling, both key regulators of the proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. <b>Results:</b> The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFβ-receptor-mediated signaling. Optimized HOME0 improved normal human esophageal organoid formation. In the HOME0-grown organoids, IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. <b>Conclusions:</b> HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.
Authors
- Fatemeh Momen‐Heravi (ORCID: https://orcid.org/0000-0003-4534-1450)
- Beverly R. Wuertz (ORCID: https://orcid.org/0000-0002-2583-9043)
- Samuel Flashner (ORCID: https://orcid.org/0000-0001-9796-0515)
- Uma M. Sachdeva (ORCID: https://orcid.org/0000-0002-0442-3794)
- Masataka Shimonosono (ORCID: https://orcid.org/0000-0002-9857-3338)
- Cecilia Martin (ORCID: https://orcid.org/0000-0001-7096-986X)
- Venkatram R. Atigadda (ORCID: https://orcid.org/0000-0003-0085-0403)
- William Britton (ORCID: https://orcid.org/0000-0001-6778-3693)
- Kenneth I. Weinberg (ORCID: https://orcid.org/0000-0003-1922-9131)
- Craig A. Elmets (ORCID: https://orcid.org/0000-0001-7131-4697)
- Hiroshi Nakagawa (ORCID: https://orcid.org/0000-0001-7330-4863)
- Yasuto Tomita
- Anuraag S. Parikh (ORCID: https://orcid.org/0000-0003-0968-1028)
- Frank G. Ondrey (ORCID: https://orcid.org/0000-0002-4951-9335)
- Norihiro Matsuura (ORCID: https://orcid.org/0000-0001-8956-4600)
- Andres J. Klein–Szanto (ORCID: https://orcid.org/0000-0002-5533-9402)
- Wataru Hirose (ORCID: https://orcid.org/0000-0001-9095-6951)
- Julian A. Abrams (ORCID: https://orcid.org/0000-0002-6021-9376)
- Amanda B. Muir (ORCID: https://orcid.org/0000-0003-2616-7063)
- Emilea H. Okayasu
- Masaki Morimoto (ORCID: https://orcid.org/0000-0001-5937-4056)
- Christian Y. Lee
- Mesra S. Ebadi
Institutions
- Fox Chase Cancer Center (US)
- Children's Hospital of Philadelphia (US)
- Columbia University Irving Medical Center (US)
- University of Alabama at Birmingham (US)
- Massachusetts General Hospital (US)
- Cancer Research Center (US)
- University of Minnesota Medical Center (US)
- Columbia University (US)
- University of Pennsylvania (US)
- Philadelphia University (US)
- Stanford University (US)
Publication Details
- Journal
- Biomolecules
- Published
- 2024-09-05
- DOI
- https://doi.org/10.3390/biom14091126
- Citations
- 6
- Primary Topic
- Esophageal Cancer Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.44
Funders
- American Chemical Society
- National Cancer Institute