Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli.

BACKGROUND & AIMS: Gastric Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) cells exert important functions during injury and homeostasis. Bone morphogenetic protein (BMP) signaling regulates gastric inflammation and epithelial homeostasis. We investigated if BMP signaling controls the fate of Lgr5 cells during inflammation.

METHODS

The promoter was used to express the BMP inhibitor noggin () in the stomach ( mice). Inhibition of BMP signaling in Lgr5 cells was achieved by crossing () mice to mice with floxed alleles of BMP receptor 1A ( mice). Lgr5/GFP cells were isolated using flow cytometry. Lineage tracing studies were conducted by crossing mice to mice that express and (). Infection with was used to induce inflammation. Morphology of the mucosa was analyzed by H&E staining. Distribution of H/K-adenosine triphosphatase-, IF-, Ki67-, CD44-, CD44v9-, and bromodeoxyuridine-positive cells was analyzed by immunostaining. Expression of neck and pit cell mucins was determined by staining with the lectins Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, respectively. , , , , and messenger RNAs were measured by quantitative reverse-transcription polymerase chain reaction.

RESULTS

mice showed diminished expression of in Lgr5/GFP cells. Infection of mice with led to enhanced inflammation, increased cell proliferation, parietal cell loss, and to the development of metaplasia and dysplasia. Infected mice, but not control mice, showed the presence of tomato glands lining the lesser curvature that stained positively with Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, and with anti-IF, -CD44, -CD44v9, and -bromodeoxyuridine antibodies.

CONCLUSIONS

Inflammation and inhibition of BMP signaling activate Lgr5 cells, which give rise to metaplastic, dysplastic, proliferating lineages that express markers of mucus neck and zymogenic cell differentiation.