Regulation of Parietal Cell Homeostasis by Bone Morphogenetic Protein Signaling

Abstract

<h3>Background and Aims</h3> Loss of bone morphogenetic protein (BMP) signaling in the stomach, achieved by transgenic expression of the BMP inhibitor noggin (<i>H</i>⁺<i>/K</i>⁺<i>-Nog</i> 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. <h3>Methods</h3> Mice with floxed alleles of BMP receptor 1a (<i>Bmpr1a</i>^flox/flox mice) were crossed to <i>H</i>⁺<i>/K</i>⁺<i>-Cre</i> mice to generate <i>H</i>⁺<i>/K</i>⁺<i>-Cre;Bmpr1a</i>^flox/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 <i>Nog</i>-expressing mice was achieved by crossing <i>H</i>⁺<i>/K</i>⁺<i>-Nog</i> mice to <i>Rosa26-tdTomato</i> (Tom) mice to generate <i>H</i>⁺<i>/K</i>⁺<i>-Nog;Rosa26-tdTom</i> mice. <i>H</i>⁺<i>/K</i>⁺<i>-Cre</i> mice were then crossed to <i>H</i>⁺<i>/K</i>⁺<i>-Nog;Rosa26-tdTom</i> mice to generate <i>H</i>⁺<i>/K</i>⁺<i>-Cre;H</i>⁺<i>/K</i>⁺<i>-Nog;Rosa26-tdTom</i> mice. Tom-labeled PCs were purified by flow cytometry. Changes in PC transcripts were measured by RNA-Seq. <h3>Results</h3> Six-month-old <i>H</i>⁺<i>/K</i>⁺<i>-Cre;Bmpr1a</i>^flox/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. <h3>Conclusion</h3> PC-specific loss of BMP signaling alters the homeostasis of the gastric epithelium leading to the development of metaplasia.