Proliferation and Differentiation of Gastric Mucous Neck and Chief Cells During Homeostasis and Injury-induced Metaplasia

Abstract

Background & Aims: Adult zymogen-producing (zymogenic) chief cells (ZCs) in the mammalian gastric gland base are believed to arise from descending mucous neck cells, which arise from stem cells. Gastric injury, such as from Helicobacter pylori infection in patients with chronic atrophic gastritis, can cause metaplasia, characterized by gastric cell expression of markers of wound-healing; these cells are called spasmolytic polypeptide-expressing metaplasia (SPEM) cells. We investigated differentiation and proliferation patterns of neck cells, ZCs, and SPEM cells in mice.Methods: C57BL/6 mice were given intraperitoneal injections of high-dose tamoxifen to induce SPEM or gavaged with H pylori (PMSS1) to induce chronic gastric injury. Mice were then given pulses of 5-bromo-2'-deoxyuridine (BrdU) in their drinking water, followed by chase periods without BrdU, or combined with intraperitoneal injections of 5-ethynyl-2'-deoxyuridine. We collected gastric tissues and performed immunofluorescence and immunohistochemical analyses to study gastric cell proliferation, differentiation, and turnover.Results: After 8 weeks of continuous BrdU administration, less than 10% of homeostatic ZCs incorporated BrdU whereas 88% of neck cells were labeled. In pulse-chase experiments, various chase periods decreased neck cell label but did not increase labeling of ZCs. When mice were given BrdU at the same time as tamoxifen, more than 90% of cells were labeled in all gastric lineages. After 3 months' recovery (no tamoxifen), ZCs became the predominant BrdU-labeled population whereas other cells-including neck cells-were mostly negative. When we tracked the labeled cells in such mice over time, we observed that the proportion of BrdU-positive ZCs

ANKRD22 Drives Rapid Proliferation of Lgr5+ Cells and Acts as a Promising Therapeutic Target in Gastric Mucosal Injury

“…Active Lgr5 þ gastric EPCs are responsible for the selfrenewal of normal gastric epithelial cells and contribute to the repair of damaged gastric mucosa. [20][21][22] However, the molecular mechanism underlying the repair of gastric mucosal damage by EPCs has not yet been elucidated clearly. 23 ANKRD22 is a reprogramming-related protein present in the colorectal cancer-initiating cells and Lgr5 þ intestinal stem cells.…”

Modulation of Stem Cell Progeny by Probiotics during Regeneration of Gastric Mucosal Erosions

“…This is not unexpected since zymogenic cells originate from neck cells which in turn come from the isthmal pre-neck cell progenitors and therefore all three cell types belong to the same lineage [62]. This does not exclude the fact that a small proportion of zymogenic cells originates from their own mitosis [62,63]. In humans, mild to severe inflammatory reaction in the gastric mucosa is also associated with a decrease in pepsinogen level leading to precancerous and cancerous changes [64].…”

Gastric Stem Cells: Physiological and Pathological Perspectives

“…Cell populations contributing to SPEM formation is partially understood. Some evidence indicate a link between SPEM development and mucus neck cells, chief cell transdifferentiation and even the isthmus stem cells in the corpus (Hayakawa et al, 2017a;Mills and Goldenring, 2017;Burclaff et al, 2020). During IM, expression of stem cell marker-Sox2 is reduced while intestinal marker (Cdx1 and Cdx2) emerges ectopically (Tsukamoto et al, 2004); and lineage tracing by following mutations in mitochondria DNA demonstrates the clonal expansion of IM by fission (McDonald et al, 2008).…”