Histological Localization of Newly-formed Desoxyribonucleic Acid

Leblond, C. P.; Stevens, C. E.; Bogoroch, Rita

doi:10.1126/science.108.2811.531

Cited by 104 publications

(15 citation statements)

References 4 publications

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“…40–42 In the gastric antrum, it has been suggested that the anatomical narrowing at the lower third of the gland, known as the isthmus, is the site of cellular renewal, and that immature cells migrate and differentiate bidirectionally from this point. 43–45 Proliferation rate of antral isthmal cells are reported to be approximately 37%, 44 which seems equivalent to antral CCK2R+ cell population (30%). The distribution and lineage tracing that we described confirms, for the first time, that CCK2R+ marks this isthmus (or +4) stem cell in the gastric antrum.…”

Section: Discussionmentioning

confidence: 95%

CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

Hayakawa

Jin

Wang

et al. 2014

Gut

115

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Objective Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. Design We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. Results Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5neg or low cell population but was distinct from typical antral Lgr5high stem cells. Treatment with progastrin interconverts Lgr5neg or low CCK2R+ cells into Lgr5high cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. Conclusions CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.

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Section: Discussionmentioning

confidence: 95%

CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis

Hayakawa

Jin

Wang

et al. 2014

Gut

115

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“…17 In the stomach, radiolabeled cells appeared just below the pits or foveolae, the microscopic openings of gastric gland units into the stomach lumen. The investigators concluded that this region of anatomic narrowing, the isthmus, was the site of cellular renewal in undamaged tissue (Figures 1 and 2).…”

Section: Stem Cell Propertiesmentioning

confidence: 99%

Gastric Epithelial Stem Cells

2011

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Advances in our understanding of stem cells in the gastrointestinal tract include the identification of molecular markers of stem and early progenitor cells in the small intestine. Although gastric epithelial stem cells have been localized, little is known about their molecular biology. Recent reports describe the use of inducible Cre recombinase activity to indelibly label candidate stem cells and their progeny in the distal stomach, (ie, the antrum and pylorus). No such lineage labeling of epithelial stem cells has been reported in the gastric body (corpus). Among stem cells in the alimentary canal, those of the adult corpus are unique in that they lie close to the lumen and increase proliferation following loss of a single mature progeny lineage, the acid-secreting parietal cell. They are also unique in that they neither depend on Wnt signaling nor express the surface marker Lgr5. Because pathogenesis of gastric adenocarcinoma has been associated with abnormal patterns of gastric differentiation and with chronic tissue injury, there has been much research on the response of stomach epithelial stem cells to inflammation. Chronic inflammation, as induced by infection with Helicobacter pylori, affects differentiation and promotes metaplasias. Several studies have identified cellular and molecular mechanisms in spasmolytic polypeptide–expressing (pseudopyloric) metaplasia. Researchers have also begun to identify signaling pathways and events that take place during embryonic development that eventually establish the adult stem cells to maintain the specific features and functions of the stomach mucosa. We review the cytologic, molecular, functional, and developmental properties of gastric epithelial stem cells.

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“…In 1948, studies using incorporation of labeled nucleotides suggested that renewal of gastric cells was driven by one or a few cells in the isthmus of both the corpus and the pyloric antrum (Leblond et al 1948). The first evidence for multipotent stem cells in stomach epithelium came from "inverse tracing" with transgenic Rosa26…”

Section: Gastric Stem Cellsmentioning

confidence: 99%