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Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium
José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills
José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills
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Research Article Cell biology Gastroenterology

Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium

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Abstract

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.

Authors

José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills

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Figure 7

Loss of chief cell–specific Adar1 does not affect metaplastic gene expression but limits proliferation during chronic H. pylori infection.

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Loss of chief cell–specific Adar1 does not affect metaplastic gene expre...
(A) Adar1fl/fl Mist1Cre-ERT/+ mice were either mock-infected or infected with H. pylori (Hp) for 10 months to induce metaplasia, followed by 7 days of either vehicle or low-dose tamoxifen (LD-Tam) treatment to induce Cre-mediated deletion of Adar1 from chief cells. Mice were euthanized 4 days later. (B) During chronic H. pylori infection, Adar1-deficient chief cells (bottom) acquire metaplastic changes similar to chronically infected Adar1-sufficient chief cells (middle). Representative metaplastic gland bases (right panels) are shown. Scale bars, 50 μm (left panels), 10 μm (right panels). (C) Adar1-deficient chief cells show decreased Ki-67 staining following H. pylori infection (bottom), compared with chronically infected Adar1-sufficient chief cells (top). Representative gland bases (right panels) are shown. Scale bars, 50 μm (left panels), 5 μm (right panels). For B and C, images are representative of 2 mice per experimental treatment. (D) The distributions of Ki-67–positive cells at the gland base following H. pylori infection of mice with Adar1-sufficient (blue) or -deficient (red) chief cells are shown. Each data point represents a randomly selected field. No significant difference was seen between the distributions of H. pylori–infected mice with Adar1-deficient chief cells, but all H. pylori–infected mice with Adar1-deficient chief cells had significantly fewer Ki-67–positive cells at the gland base compared with H. pylori–infected mice with Adar1-sufficient chief cells. Few, if any, Ki-67–positive chief cells could be appreciated in mock-infected mice with Adar1-deficient chief cells, and this number was not determined. P values were calculated by 1-way ANOVA using Tukey’s multiple comparisons test. A statistically significant difference (P = 0.0022) was also found between H. pylori-infected, Adar1-sufficient and -deficient mice by Mann-Whitney test.

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