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.
View: Text | PDF
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

×

Figure 2

BMP activation inhibits proliferation and induces squamous differentiation of primary mouse basal progenitor cells in vitro.

Options: View larger image (or click on image) Download as PowerPoint
BMP activation inhibits proliferation and induces squamous differentiati...
(A) BMP4 treatment for 5 days induced the expression of the differentiation marker involucrin in basal progenitor cells. (B) BMP4 treatment led to increased protein levels of involucrin, loricrin, and p-SMAD1/5/8 as shown by Western blot analysis. Actin served as a loading control. (C and D) Proliferation of the epithelium was inhibited by BMP4 treatment. Proliferating cells were labeled with p-H3. Data in D show that the proportion of p-H3 plus vehicle cells in all epithelial cells was significantly reduced after BMP4 treatment (n = 3). (E) Knockdown of follistatin promoted squamous differentiation of basal progenitor cells as indicated by involucrin staining. (F) Knockdown of follistatin led to increased involucrin and loricrin transcript levels (n = 3). Data represent the mean ± SEM. *P < 0.05 and **P < 0.01 by Student’s t test. Scale bars: 50 μm. Fst, follistatin; Inv, involucrin; Lor, loricrin; KD, knockdown.