Gastric stem cells are located in the isthmus of the gastric glands and give rise to epithelial progenitors that undergo bipolar migration and differentiation into pit and oxyntic lineages. Although gastric mucus neck cells located below the isthmus express trefoil factor family 2 (TFF2) protein, TFF2 messenger RNA transcripts are concentrated in cells above the neck region in normal corpus mucosa, suggesting that TFF2 transcription is a marker of gastric progenitor cells.

Using a BAC strategy, we generated a transgenic mouse with a tamoxifen-inducible Cre under the control of the TFF2 promoter (TFF2-BAC-Cre^ERT2) and analyzed the lineage derivation from TFF2 mRNA transcript–expressing (TTE) cells.

TTE cells were localized to the isthmus, above and distinct from TFF2 protein-expressing mucus neck cells. Lineage tracing revealed that these cells migrated toward the bottom of the gland within 20 days, giving rise to parietal, mucous neck, and chief cells, but not to enterochromaffin-like-cell. Surface mucus cells were not derived from TTE cells and the progeny of the TTE lineage did not survive beyond 200 days. TTE cells were localized in the isthmus adjacent to doublecortin CaM kinase-like–1⁺ putative progenitor cells. Induction of spasmolytic polypeptide-expressing metaplasia with DMP-777–induced acute parietal cell loss revealed that this metaplastic phenotype might arise in part through transdifferentiation of chief cells as opposed to expansion of mucus neck or progenitor cells.

TFF2 transcript–expressing cells are progenitors for mucus neck, parietal and zymogenic, but not for pit or enterochromaffin-like cell lineages in the oxyntic gastric mucosa.