The origin of pre-neoplastic metaplasia in the stomach: chief cells emerge from the Mist

Abstract

The digestive-enzyme secreting, gastric epithelial chief (zymogenic) cell is remarkable and underappreciated. Here, we discuss how all available evidence suggests that mature chief cells in the adult, mammalian stomach are postmitotic, slowly turning over cells that arise via a relatively long-lived progenitor, the mucous neck cell, The differentiation of chief cells from neck cells does not involve cell division, and the neck cell has its own distinct pattern of gene expression and putative physiological function. Thus, the ontogeny of the normal chief cell lineage exemplifies transdifferentiation. Furthermore, under pathophysiogical loss of acid-secreting parietal cell, the chief cell lineage can itself trasndifferentiate into a mucous cell metaplasia designated Spasmolytic Polypeptide Expressing Metaplasia (SPEM). Especially in the presence of inflammation, this metaplastic lineage can regain proliferative capacity and, in humans may also further differentiate into intestinal metaplasia. The results indicate that gastric fundic lineages display remarkable plasticity in both physiological ontogeny and pathophysiological pre-neoplastic metaplasia.

Figure 1. The cellular lineage ontogeny of normal gastric chief cells

A. Scheme for the origin of chief cell lineages from mucous neck cells. B. Transcription factor cascade responsible for maturation of normal chief cells.

Figure 2. Current model for the origin and progression of gastric metaplasias

The preponderance of data indicates that chief cell transdifferentiation into SPEM is triggered by loss of parietal cells in the fundic mucosa. In the face of inflammation, SPEM can expand into a proliferative metaplasia. With continued chronic inflammation, intestinal metaplasia evolves in the setting of pre-existing SPEM and can come to dominate the entirety of the glands.