Characterization of the metaplastic process in the stomach using in vivo models and novel normal and metaplastic gastric cell lines

Abstract

Chronic Helicobacter pylori infection in humans causes prominent inflammation and oxyntic atrophy, which leads to two distinct types of metaplasia: intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM). Recent investigations have shown oxyntic atrophy results in the transdifferentiation of chief cells into SPEM cells. While both metaplasias have been associated with gastric adenocarcinoma, the progression of metaplasia to neoplasia remains obscure. Murine models of SPEM were utilized to examine the metaplastic progression. To identify the commonalities and differences between phenotypic SPEM lineages, SPEM cells were compared from three mouse models of parietal cell loss with (Helicobacter felis infection and L635 administration) and without inflammation (DMP-777 administration). Transcript expression patterns demonstrated differences among the phenotypic SPEM models. While some markers are expressed in all phenotypic SPEM lineages, distinct patterns of intestinal gene expression are present in murine metaplasia associated with inflammation indicative of metaplastic progression towards a more intestinalized metaplastic phenotype. These studies identified an advanced metaplasia in mice, called SPEM with intestinal characteristics (SPEM-IC), the murine analog to intestinal metaplasia in humans. Additionally, the necessity of mature chief cells for transdifferentiation into SPEM was examined by administering DMP-777 or L635 to Mist1 null mice, which lack the secretory machinery critical for complete chief cell maturation. Induction of SPEM from immature chief cells in Mist1 null mice was impeded. Thus, mature chief cells with established secretory machinery are necessary for transdifferentiation into SPEM. However, more in-depth studies into molecular mechanisms were hindered by a lack of in vitro cell models of chief cells and SPEM. Utilizing the Immortomouse, novel chief cell (ImChief) and SPEM (ImSPEM) cultures were established and provide indispensible in vitro models for studying cellular characteristics of metaplasia and molecular mechanisms of the metaplastic progression in the stomach. The work presented here has lead to a broader understanding of the mechanisms involved in chief cell transdifferentiation into SPEM and the metaplastic progression. Furthermore, these studies have identified novel metaplasia markers as well as established in vitro cell models of chief cells and SPEM.