title: BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis.
abstract: Tissue homeostasis requires balanced self-renewal and differentiation of stem/progenitor cells, especially in tissues that are constantly replenished like the esophagus. Disruption of this balance is associated with pathological conditions, including eosinophilic esophagitis (EoE), in which basal progenitor cells become hyperplastic upon proinflammatory stimulation. However, how basal cells respond to the inflammatory environment at the molecular level remains undetermined. We previously reported that the bone morphogenetic protein (BMP) signaling pathway is critical for epithelial morphogenesis in the embryonic esophagus. Here, we address how this pathway regulates tissue homeostasis and EoE development in the adult esophagus. BMP signaling was specifically activated in differentiated squamous epithelium, but not in basal progenitor cells, which express the BMP antagonist follistatin. Previous reports indicate that increased BMP activity promotes Barrett's intestinal differentiation; however, in mice, basal progenitor cell-specific expression of constitutively active BMP promoted squamous differentiation. Moreover, BMP activation increased intracellular ROS levels, initiating an NRF2-mediated oxidative response during basal progenitor cell differentiation. In both a mouse EoE model and human biopsies, reduced squamous differentiation was associated with high levels of follistatin and disrupted BMP/NRF2 pathways. We therefore propose a model in which normal squamous differentiation of basal progenitor cells is mediated by BMP-driven NRF2 activation and basal cell hyperplasia is promoted by disruption of BMP signaling in EoE.
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Wei-Yao
authors.initials: WY
authors.lastname: Ku
authors.forename: Zhongren
authors.initials: Z
authors.lastname: Zhou
authors.forename: Evan S
authors.initials: ES
authors.lastname: Dellon
authors.forename: Gary W
authors.initials: GW
authors.lastname: Falk
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Mei-Lun
authors.initials: ML
authors.lastname: Wang
authors.forename: Kuancan
authors.initials: K
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: David A
authors.initials: DA
authors.lastname: Katzka
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Peters
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Lan
authors.forename: Jianwen
authors.initials: J
authors.lastname: Que
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000096:biosynthesis / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D057765:Eosinophilic Esophagitis / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism; D004947:Esophagus / Q000166:cytology* / Q000254:growth & development; D038681:Follistatin / Q000502:physiology; D017930:Genes, Reporter; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; C503233:FST protein, human; D038681:Follistatin; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D011498:Protein Precursors; D017382:Reactive Oxygen Species; C032253:involucrin; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I