New insights into the stem cells and the precursors of the gastric epithelium.

It is believed that stomach neoplasia represents the end result of a multistep journey that starts with derangement of the cellular proliferation and commitment program of the epithelium. The epithelium is normally made up of a single layer of cells that invaginates to form numerous short pits continuous with long tubular glands divisible into isthmus, neck, and base regions. Three main cell lineages populate these pit-gland units: 1) mucus-secreting pit, 2) pepsinogen-secreting zymogenic, and 3) acid-secreting parietal cell lineages. The immature cells of the unit are located in the isthmus region; they include undifferentiated stem cells that undergo frequent asymmetric mitosis to reproduce themselves and give rise to two partially committed precursors: 1) prepit-cell precursors, which become prepit cells in the isthmus and then migrate outward into the pit and mature into pit cells, and 2) preneck cell precursors, which become preneck cells in the isthmus and then migrate inward to the neck region and transform into neck cells. The latter continue their inward migration and eventually reach the base region where they gradually change their phenotype through a prezymogenic step to become zymogenic cells. The stem cells, as well as the prepit and preneck cell precursors, share in the production of preparietal cells that, in the isthmus, mature into parietal cells and then migrate outward into the pit or inward into the neck and base. The stem cells also give rise to preenteroendocrine and precaveolated cells. These become, respectively, enteroendocrine and caveolated cells that proceed to follow the bidirectional migratory route of parietal cells. The production of rare nonproliferating preparietal cells is enhanced after blocking the secretory activity of their mature forms by continuous infusion of the histamine H2-receptor antagonist, ranitidine, for 42 h. Thus, the presence of active mature parietal cells is necessary to maintain the normal cellular proliferation and commitment program in the gastric epithelium.