BMP-driven NRF2 activation in esophageal basal cell differentiation and eosinophilic esophagitis
Ming Jiang, … , Xiaopeng Lan, Jianwen Que
Ming Jiang, … , Xiaopeng Lan, Jianwen Que
Published March 16, 2015
Citation Information: J Clin Invest. 2015;125(4):1557-1568. https://doi.org/10.1172/JCI78850.
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Research Article Gastroenterology

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

Ming Jiang, Wei-Yao Ku, Zhongren Zhou, Evan S. Dellon, Gary W. Falk, Hiroshi Nakagawa, Mei-Lun Wang, Kuancan Liu, Jun Wang, David A. Katzka, Jeffrey H. Peters, Xiaopeng Lan, Jianwen Que

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Figure 8

Follistatin is a direct downstream target of the IL-13/STAT6 signaling pathway.

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Follistatin is a direct downstream target of the IL-13/STAT6 signaling p...
(A) The follistatin promoter region contains 2 potential STAT6-binding sites within longer, conserved DNA sequences. Sequence comparison revealed the conservation of these 2 STAT6-binding sites in various species. The STAT6-binding sites are highlighted by black boxes. (B) IL-13 treatment significantly increased the promoter activity of the follistatin gene that contains 2 STAT6-binding sites in human EPC2 cells (n = 3). Note that removal of the 2 STAT6-binding sites abrogated the effects induced by IL-13 treatment. The promoter region with or without the 2 STAT6-binding sites was cloned into the pGL3 luciferase reporter and is designated as P1 and P2, respectively. (C) BMP activation promotes squamous differentiation of basal progenitor cells through crosstalk with ROS-activated NRF2 signaling. The BMP inhibitor follistatin protects basal cells from BMP activation initiated by BMP7 and possibly by BMP4 as well. Lack of follistatin in suprabasal cells leads to BMP activation and increases intracellular ROS levels. Subsequent activation of NRF2 signaling promotes squamous differentiation of basal progenitor cells. (D) Basal cell hyperplasia in the IL-13 overexpression–induced mouse EoE model and in human biopsies was associated with increased levels of follistatin and decreased BMP activation. Note that BMP7 was present in all of the epithelium, while BMP4 was expressed by subpopulations of basal progenitor cells (#). Data represent the mean ± SEM. *P < 0.05 by Student’s t test. BC, basal cell; FST, follistatin; RE1, response element 1; RE2, response element 2; SBC, suprabasal cell; ve, vehicle.