title: Esophageal epithelial cells acquire functional characteristics of activated myofibroblasts after undergoing an epithelial to mesenchymal transition.
abstract: OBJECTIVE
  Eosinophilic esophagitis (EoE) is an allergic inflammatory disease that leads to esophageal fibrosis and stricture. We have recently shown that in EoE, esophageal epithelial cells undergo an epithelial to mesenchymal transition (EMT), characterized by gain of mesenchymal markers and loss of epithelial gene expression. Whether epithelial cells exposed to profibrotic cytokines can also acquire the functional characteristics of activated myofibroblasts, including migration, contraction, and extracellular matrix deposition, is relevant to our understanding and treatment of EoE-associated fibrogenesis. In the current study, we characterize cell migration, contraction, and collagen production by esophageal epithelial cells that have undergone cytokine-induced EMT in vitro.
  
  
  RESULTS
  Stimulation of human non-transformed immortalized esophageal epithelial cells (EPC2-hTERT) with profibrotic cytokines TNFα, TGFβ, and IL1β for three weeks led to acquisition of mesenchymal αSMA and vimentin, and loss of epithelial E-cadherin expression. Upon removal of the profibrotic stimulus, epithelial characteristics were partially rescued. TGFβ stimulation had a robust effect upon epithelial collagen production. Surprisingly, TNFα stimulation had the most potent effect upon cell migration and contraction, exceeding the effects of the prototypical profibrotic cytokine TGFβ. IL1β stimulation alone had minimal effect upon esophageal epithelial migration, contraction, and collagen production.
  
  
  CONCLUSIONS
  Esophageal epithelial cells that have undergone EMT acquire functional characteristics of activated myofibroblasts in vitro. Profibrotic cytokines exert differential effects upon esophageal epithelial cells, underscoring complexities of fibrogenesis in EoE, and implicating esophageal epithelial cells as effector cells in EoE-associated fibrogenesis.
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA. Electronic address: muira@email.chop.edu.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Muir
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Dods
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA.
authors.forename: Yuli
authors.initials: Y
authors.lastname: Noah
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA.
authors.forename: Sarit
authors.initials: S
authors.lastname: Toltzis
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA.
authors.forename: Prasanna Modayur
authors.initials: PM
authors.lastname: Chandramouleeswaran
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Lee
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Benitez
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Bedenbaugh
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Falk
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Rebecca G
authors.initials: RG
authors.lastname: Wells
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, The Children׳s Hospital of Philadelphia, Philadelphia, PA 19104 USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 USA.
authors.forename: Mei-Lun
authors.initials: ML
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D004947:Esophagus / Q000166:cytology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000199:Actins; D015820:Cadherins; D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen