Regulation of Parietal Cell Homeostasis by Bone Morphogenetic Protein Signaling

Abstract

Background and Aims: Loss of bone morphogenetic protein (BMP) signaling in the stomach, achieved by transgenic expression of the BMP inhibitor noggin (H+/K+-Nog mice), causes parietal cell (PC) loss, spasmolytic polypeptide-expressing metaplasia, a marker of preneoplasia, and activation of cell proliferation. We examined if specific inhibition of BMP signaling in PCs leads to aberrations in epithelial homeostasis. Methods: Mice with floxed alleles of BMP receptor 1a (Bmpr1aflox/flox mice) were crossed to H+/K+-Cre mice to generate H+/K+-Cre;Bmpr1aflox/flox mice. Morphology of the mucosa was analyzed by hematoxylin and eosin staining. Distribution of H+/K+-ATPase-, IF-, and Ki-67-positive cells was analyzed by immunostaining. Expression of pit and neck cell mucins was determined by staining with the lectins Ulex Europaeus Agglutinin 1 and Griffonia (Bandeiraea) simplicifolia lectin II, respectively. Isolation of PCs from control and Nog-expressing mice was achieved by crossing H+/K+-Nog mice to Rosa26-tdTomato (Tom) mice to generate H+/K+-Nog;Rosa26-tdTom mice. H+/K+-Cre mice were then crossed to H+/K+-Nog;Rosa26-tdTom mice to generate H+/K+-Cre;H+/K+-Nog;Rosa26-tdTom mice. Tom-labeled PCs were purified by flow cytometry. Changes in PC transcripts were measured by RNA-Seq. Results: Six-month-old H+/K+-Cre;Bmpr1aflox/flox mice exhibited increased epithelial cell proliferation, presence of transitional cells showing colocalization of IF with both Griffonia (Bandeiraea) simplicifolia lectin II-binding mucins and the H+/K+-ATPase, and expansion of Ulex Europaeus Agglutinin 1-positive cells. PC transcripts from Nog-expressing mice demonstrated induction of markers of Spasmolytic Polypeptide-Expressing Metaplasia. Conclusion: PC-specific loss of BMP signaling alters the homeostasis of the gastric epithelium leading to the development of metaplasia.

Keywords

• Dysplasia
• Differentiation
• Metaplasia
• RNA-Seq