TFF2 mRNA Transcript Expression Marks a Gland Progenitor Cell of the Gastric Oxyntic Mucosa

Abstract

Background and Aims 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. While gastric mucus neck cells, located below the isthmus, express trefoil factor family 2 (TFF2) protein, TFF2 mRNA transcripts are concentrated in cells above the neck region in normal corpus mucosa, suggesting that TFF2 transcription is a marker of gastric progenitor cells. Methods Using a BAC strategy, we generated a transgenic mouse with a tamoxifen-inducible Cre under the control of the TFF2 promoter (TFF2-BAC-CreERT2) and analyzed the lineage derivation from TFF2 mRNA transcript-expressing (TTE) cells. Results TTE cells were localized to the isthmus, above and distinct from TFF2 protein-expressing mucus neck cells. Lineage tracing revealed that these cells migrated towards the bottom of the gland within 20 days, giving rise to parietal, mucous neck and chief cells, but not to ECL cells. 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 Dclk1+ putative progenitor cells. Induction of spasmolytic polypeptide-expressing metaplasia (SPEM) with DMP-777-induced acute parietal cell loss revealed that this metaplastic phenotype might arise in part through transdiferentiation of chief cells as opposed to expansion of mucus neck or progenitor cells. Conclusion TFF2-transcript-expressing cells are progenitors for mucus neck, parietal and zymogenic, but not for pit or ECL cell lineages in the oxyntic gastric mucosa.

Identification of Lineage-Uncommitted, Long-Lived, Label-Retaining Cells in Healthy Human Esophagus and Stomach, and in Metaplastic Esophagus

“…Previously, it is only in the oxyntic mucosa of trefoil factor-2 (TFF2) mice that successful lineage tracing has demonstrated progenitor stem cells in animal models 26 . Furthermore it has also been reported that the murine small intestinal and colonic crypt base columnar cells (CBCs) expressing lgr5, are actively cycling and are able to regenerate the entire cell population.…”

Long-lived intestinal tuft cells serve as colon cancer–initiating cells

“…BAC recombination was performed using the CreTM-FrtNeoFrt or the EGFPcre-Frt-kanFrt (pIGCN21) cassette, as described previously (65). Briefly, the CreTMFrtNeoFrt cassette was ligated into a p451 plasmid before generating a probe containing a 40-bp sequence homologous to the BAC sequence directly upstream of the ATG in exon 2 (Supplemental Figure 1).…”

Gastric Cancer: A Stem Cell Disease?

“…In the corpus, some studies suggested that Sox2 + cells may represent long-lived stem cells scatered throughout the isthmus and in the lower part of the gastric unit [9]. Trefoil factor family 2 (Tf2 + ) cells were also described as shortlived progenitors in the isthmus region of the corpus [10]. More recently, lineage tracing experiments have shown that diferentiated mature chief cells expressing the Troy marker at the base of the corpus gastric glands can generate entirely labeled gastric units over a period of several months in vivo and long-lived organoids in vitro [11].…”