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 4

Activation of BMP signaling increases intracellular ROS levels and NRF2 activity.

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Activation of BMP signaling increases intracellular ROS levels and NRF2 ...
(A) BMP4 treatment altered the activity of multiple intracellular signaling pathways including the NRF2-mediated oxidative stress pathway (arrow) in EPC2 cells. (B) BMP4 treatment promoted NRF2-mediated transcriptional activation as revealed by the ARE reporter assay. EPC2 cells expressing the carrier vector pGL3 were used as controls (n = 3). Luc, luciferase; RLA, relative luciferase activity. (C) BMP4 treatment increased the transcript levels of Nqo1, a NRF2 downstream target, which was accompanied by increased levels of involucrin and loricrin (n = 3). BMP4 treatment also increased p-NRF2, involucrin, and loricrin protein levels. Note that there were no significant changes in total Nrf2 transcript levels. (D) BMP4 treatment increased ROS levels in a time-dependent manner as visualized by DCF fluorescence intensity, while the presence of the BMP antagonist follistatin inhibited BMP4-induced ROS production. Data represent the average fluorescence intensity from 3 individual experiments. (E) BMP4 treatment increased Nox4 transcript levels, indicating increased intracellular ROS in EPC2 cells as measured by real-time PCR (n = 3). (F and G) BMP activation promoted nuclear accumulation of p-NRF2 in esophageal basal progenitor cells from Krt5-CreER R26caBmpr1a mutants. Note that p-NRF2 was enriched in the differentiated suprabasal cells of the control esophagus. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 by Student’s t test. Scale bars: 50 μm.