Regulation of Parietal Cell Homeostasis by Bone Morphogenetic Protein Signaling

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.

Mice with floxed alleles of BMP receptor 1a (Bmpr1a mice) were crossed to H /K -Cre mice to generate H /K -Cre;Bmpr1a 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.

Six-month-old H /K -Cre;Bmpr1a 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.

PC-specific loss of BMP signaling alters the homeostasis of the gastric epithelium leading to the development of metaplasia.