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BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

The Journal of clinical investigation, 2015-04, Vol.125 (4), p.1557-1568 [Peer Reviewed Journal]

COPYRIGHT 2015 American Society for Clinical Investigation ;COPYRIGHT 2015 American Society for Clinical Investigation ;Copyright American Society for Clinical Investigation Apr 2015 ;Copyright © 2015, American Society for Clinical Investigation 2015 American Society for Clinical Investigation ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/JCI78850 ;PMID: 25774506

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Title:
BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis
Author: Jiang, Ming ; Ku, Wei-Yao ; Zhou, Zhongren ; Dellon, Evan S ; Falk, Gary W ; Nakagawa, Hiroshi ; Wang, Mei-Lun ; Liu, Kuancan ; Wang, Jun ; Katzka, David A ; Peters, Jeffrey H ; Lan, Xiaopeng ; Que, Jianwen
Subjects: Animals ; Biopsy ; Bone Morphogenetic Protein Receptors, Type I - biosynthesis ; Bone Morphogenetic Protein Receptors, Type I - genetics ; Bone Morphogenetic Proteins - biosynthesis ; Bone Morphogenetic Proteins - genetics ; Bone Morphogenetic Proteins - physiology ; Cell Differentiation ; Cells, Cultured ; Cytokines ; Development and progression ; Disease ; Eosinophilic Esophagitis - metabolism ; Eosinophilic Esophagitis - pathology ; Epithelial Cells - metabolism ; Esophagus - cytology ; Esophagus - growth & development ; Follistatin - physiology ; Gastroesophageal reflux ; Genes, Reporter ; Genetic aspects ; Health aspects ; Humans ; Hyperplasia ; Laboratories ; Ligands ; Mice ; Mice, Inbred C57BL ; Morphogenesis ; NF-E2-Related Factor 2 - physiology ; Oxidative Stress ; Protein Precursors - biosynthesis ; Protein Precursors - genetics ; Reactive Oxygen Species - metabolism ; Rodents ; Signal Transduction - physiology ; Stem cells ; Studies ; Transcription factors
Is Part Of: The Journal of clinical investigation, 2015-04, Vol.125 (4), p.1557-1568
Description: 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.
Publisher: United States: American Society for Clinical Investigation
Language: English
Identifier: ISSN: 0021-9738
EISSN: 1558-8238
DOI: 10.1172/JCI78850
PMID: 25774506
Source: Open Access: PubMed Central
Geneva Foundation Free Medical Journals at publisher websites
AUTh Library subscriptions: ProQuest Central
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BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis

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