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 1

BMP signaling activity in the stratified squamous epithelium of the adult mouse esophagus.

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BMP signaling activity in the stratified squamous epithelium of the adul...
(A and B) BMP signaling is active in differentiated suprabasal cells, but not in basal progenitor cells, as shown by the BMP reporter allele BRE-lacZ. The undifferentiated basal progenitor cells are labeled with p63. Note that some mesenchymal cells in the lamina propria were also positive for X-gal staining. Nuclei were counterstained with nuclear fast red. (C) BMP4 is expressed in subpopulations (arrows) of basal progenitor cells, as shown by the Bmp4-lacZ allele. Basal progenitor cells are labeled with the SOX2 transcription factor. (D) BMP7 was expressed in all of the epithelium, including in basal and suprabasal cells, as demonstrated by the Bmp7-lacZ allele. (E) The BMP inhibitor follistatin was enriched in basal progenitor cells. The boxed region is shown enlarged at right (original magnification, ×40). (F) The BMP inhibitor gremlin 2 was expressed in the muscularis mucosa beneath the lamina propria layer. The boxed region is shown enlarged at right (original magnification, ×40). Dotted line in A, B, D, and E indicates the basement membrane. Ep, epithelium; Me, mesenchyme. Scale bars: 50 μm.