Role of metaplasia during gastric regeneration

Abstract

Spasmolytic polypeptide/trefoil factor 2 (TFF2)-expressing metaplasia (SPEM) is a mucous-secreting reparative lineage that emerges at the ulcer margin in response to gastric injury. Under conditions of chronic inflammation with parietal cell loss, SPEM has been found to emerge and evolve into neoplasia. Cluster-of-differentiation gene 44 (CD44) is known to coordinate normal and metaplastic epithelial cell proliferation. In particular, CD44 variant isoform 9 (CD44v9) associates with the cystine-glutamate transporter xCT, stabilizes the protein, and provides defense against reactive oxygen species (ROS). xCT stabilization by CD44v9 leads to defense against ROS by cystine uptake, glutathione (GSH) synthesis, and maintenance of the redox balance within the intracellular environment. Furthermore, p38 signaling is a known downstream ROS target, leading to diminished cell proliferation and migration, two vital processes of gastric epithelial repair. CD44v9 emerges during repair of the gastric epithelium after injury, where it is coexpressed with other markers of SPEM. The regulatory mechanisms for the emergence of CD44v9 and the role of CD44v9 during the process of gastric epithelial regeneration are largely unknown. Inflammation and M2 macrophage infiltration have recently been demonstrated to play key roles in the induction of SPEM after injury. The following review proposes new insights into the functional role of metaplasia in the process of gastric regeneration in response to ulceration. Our insights are extrapolated from documented studies reporting oxyntic atrophy and SPEM development and our current unpublished findings using the acetic acid-induced gastric injury model.

Keywords: CD44 variant isoform 9; cystine-glutamate transporter; gastric ulcers; spasmolytic polypeptide-expressing metaplasia.

Fig. 1.

Representative histology of the injured site within the mouse stomach. Hematoxylin and eosin stain showing metaplastic glands at the ulcer margin and areas of granulation tissue and the ulcer site. Scale bar = 50 μm.

Fig. 2.

Schematic diagram showing the progression of gastric wound healing. A: injury of the gastric epithelium either via chronic nonsteroidal anti-inflammatory drug (NSAID) use or inflammation results in ablation of the gastric epithelium and obvious ulcer margins. B: during the early stages of regeneration there is the emergence of the granulation tissue with infiltrating macrophages and the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM). It is still unknown whether the SPEM glands at the ulcer margins arise from the transdifferentiation of the chief cells to a metaplastic phenotype. Reepithelialization (C) occurs before complete regeneration (D) of the gastric epithelium and transient expression of SPEM.