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 7

Basal cell hyperplasia in human EoE biopsies is associated with reduced BMP signaling and increased follistatin levels.

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Basal cell hyperplasia in human EoE biopsies is associated with reduced ...
(A) H&E staining showed expansion of basal cells in human EoE biopsies. Arrowheads indicate eosinophilic infiltration into the epithelium. The inset is the high-magnification (original magnification, ×40) view of the boxed region. (B) Basal cell hyperplasia was associated with increased proliferation as indicated by p63 and Ki67 staining. (C) BMP activity was absent in the hyperplastic epithelium as shown by p-SMAD1/5/8 staining. (D) Nuclear localization of p-NRF2 was reduced in the EoE epithelium. (E) Basal cell hyperplasia was accompanied by enrichment of follistatin. (F) Transcript levels of IL13 were significantly increased as shown by real-time PCR. (G) Transcript levels of eotaxin-3, a downstream mediator of IL-13, were significantly increased. (H) Transcript levels of GCLC, GSTP1, and NQO1 were decreased in EoE biopsies. (I) Transcript levels of FST were significantly increased in EoE biopsies. Data represent the mean ± SEM. Fourteen biopsies for each group were included. *P < 0.05, **P < 0.01, and ****P < 0.0001 by Student’s t test. Scale bars: 50 μm.