Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

Abstract

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in Helicobacter felis-infected mice. Mongolian gerbils infected with Helicobacter pylori (Hp) develop goblet cell intestinal metaplasia and adenocarcinoma, but the presence of SPEM has not been studied in gerbils. We therefore have sought to examine the development of metaplastic mucosal changes in Hp-infected Mongolian gerbils. Mongolian gerbils were assigned to either uninfected controls or infected with Hp at 17 weeks of age. The animals were killed at 17, 20, 26, 31, 41 and 56 weeks of age. Stomach sections were stained using antibodies for TFF2, intrinsic factor, H/K-ATPase, BrdU and MUC2. Dual immunofluorescence staining for TFF2 with intrinsic factor and for TFF2 with MUC2 was performed. In uninfected animals, no SPEM or intestinal metaplasia was observed. Infected gerbils developed SPEM initially in the intermediate zone along the lesser curvature and subsequently spread out towards the greater curvature. In the earlier stages of infection, SPEM glands demonstrated TFF2 and intrinsic factor double staining cells. However, after 35 weeks of infection, the number of double staining SPEM cells decreased. While early in infection SPEM organized in straight glands, in the later stages of infections, SPEM glands became distorted or dilated along with the development of gastritis cystica profunda that was TFF2 positive. Goblet cell intestinal metaplasia developed only late in the infection. Dual staining for TFF2 and MUC2 showed glands containing both SPEM-and MUC2-positive goblet cell intestinal metaplasia. SPEM develops early in Hp infection in Mongolian gerbils, and alterations in gland morphology arise from SPEM glands during the course of gastric infection with goblet cell intestinal metaplasia developing subsequent to SPEM.

The Transcription Factor MIST1 Is a Novel Human Gastric Chief Cell Marker Whose Expression Is Lost in Metaplasia, Dysplasia, and Carcinoma

“…51 MIST1 staining assesses both lesions (the former via plasma cell staining, the latter indirectly via visualization of metaplastic changes in MIST1-positive chief cells and loss of MIST1-negative parietal cells). The demonstration of spatial heterogeneity in IM also validates animal findings 37,72,99 and expands the concept of gland-to-gland heterogeneity, established in the context of human esophageal dysplasia, 100 into the realm of metaplastic/ paracancerous lesions. Accordingly, CDX2ϩ/MIST1ϩ hybrid nuclei likely represent an initial/intermediate stage of aberrant intestinal-like differentiation.…”

“…develop gastritis cystica profunda as well as dysplasia. 14,37,39 These findings triggered demonstration of SPEM in humans 11,29,30 and, importantly, cancer association rates clearly exceed those reported for IM. 13 However, because lineage tracing and sequential analysis of differentiation cannot be easily performed in humans, 31,40 the cellular origins of human SPEM have not been established.…”

“…28,34 In animal models, chronic Helicobacter colonization induces loss of parietal cells (ie, oxyntic atrophy) and concomitant metaplasia of the basally located chief cells. 11,31,[35][36][37] Specifically, chief cells regain proliferative potential and start reexpressing progenitor markers such as TFF2, MUC6, and the epitope for the lectin Griffonia Simplificolia, GS-II. 38 Thus, in animals, initial stages of SPEM are characterized by ectopic TFF2 expression in mature chief cells in addition to markers of normal chief cell differentiation (murine intrinsic factor, Pepsinogen C [PGC]; Carboxypeptidase B [CBP1]; MIST1).…”

Stomach development, stem cells and disease

“…The parietal cell loss leads to defects in epithelial homeostasis, inducing transdifferentiation of chief cells to SPEM (Li et al, 1996;Nam et al, 2010). Accumulating data indicate that intestinal metaplasia arises from SPEM, highlighting the significance of proper lineage differentiation (Yoshizawa et al, 2007;Nam et al, 2009;Goldenring et al, 2010). It is unclear whether these effects on two or more cell types are independent or reflect the targeting of a common progenitor.…”

19 Gastric Tumor Development in SMAD3-Deficient Mice Initiates From Forestomach/Glandular Transition Zone Along the Lesser Curvature

“…Similar results are also seen in H. pylori-infected Mongolian gerbils. (37) In contrast, several genetic models including TFF1 null, gastrin null and gp130 mutant mice develop gastric dysplasia and neoplasia confined to the antrum. (38)(39)(40) The Smad3 null mouse model described in the present studies shows development of a distinctly proximal fundic dysplastic lesion that appears to arise from the first gland of the fundic mucosa along the lesser curvature of the stomach at the junction between the squamous forestomach and the glandular epithelium.…”