Mature gastric chief cells are not required for the development of metaplasia.

During human gastric carcinogenesis, intestinal metaplasia is frequently seen in the atrophic stomach. In mice, a distinct type of metaplasia known as spasmolytic polypeptide-expressing metaplasia (SPEM) is found in several inflammatory and genetically engineered models. Given the diversity of long- and short-term models of mouse SPEM, it remains unclear whether all models have a shared or distinct molecular mechanism. The origin of SPEM in mice is presently under debate. It is postulated that stem or progenitor cells acquire genetic alterations that then supply metaplastic cell clones, whereas the possibility of transdifferentiation or dedifferentiation from mature gastric chief cells has also been suggested. In this study, we report that loss of chief cells was sufficient to induce short-term regenerative SPEM-like lesions that originated from chief cell precursors in the gastric neck region. Furthermore, Lgr5+ mature chief cells failed to contribute to both short- and long-term metaplasia, whereas isthmus stem and progenitor cells efficiently contributed to long-term metaplasia. Interestingly, multiple administrations of high-dose pulsed tamoxifen induced expansion of Lgr5 expression and Lgr5-CreERT recombination within the isthmus progenitors apart from basal chief cells. Thus we conclude that short-term SPEM represents a regenerative process arising from neck progenitors following chief cell loss, whereas true long-term SPEM originates from isthmus progenitors. Mature gastric chief cells may be dispensable for SPEM development. NEW & NOTEWORTHY Recently, dedifferentiation ability in gastric chief cells during metaplasia development has been proposed. Our findings reveal that lesions that were thought to be acute metaplasia in fact represent normal regeneration supplied from neck lineage and that isthmus stem/progenitors are more responsible for sustained metaplastic changes. Cellular plasticity in gastric chief cells may be more limited than recently highlighted.

Effects of AG60 on Gastric Chief Cells of the Mouse Implanted with Ehrlich Carcinoma Cells / 대한해부학회지

This experiment was performed to evaluate the morphological responses of the gastric epithelial cells and the gastric chief cells of the mouse inoculated with Ehrlich carcinoma cells in the inguinal area following administration of acriflavine-guanosine composition (AG60). Healthy adult ICR mice were divided into normal and experimental groups. In the experimental groups, each mouse was inoculated with 1x10(7) Ehrlich carcinoma cells subcutaneously in the inguinal area. The day following the 7th injection of saline or AG60, each mouse was injected with methyl-3H-thymidine through tail vein. Seventy minutes after the thymidine injection, gastric tissues were taken and fixed in 10% buffered neutral formalin. Deparaffinized sections were coated with autoradiographic emulsion EM-1 and dried, and then placed in a light-tight box. The number of labeled epithelial cells in the gastric mucosae were observed and calculated. And for electron microscopic observation, gastric tissues were prefixed with 2.5% glutaraldehyde-1.5% paraformaldehyde solution, followed by post-fixation with 1% osmium tetroxide solution. The ultrathin sections were stained with uranyl acetate and lead citrate. The size of zymogen granules and mitochondria in the gastric chief cells were observed and calculated. On the autoradiographic study, number of labeled cells in the area of 3.5 mm width (6 micrometer thickness) of mouse gastric mucosae of normal control, tumor control and AG60-treated groups were 319.7+/-66.46, 343.7+/-47.72 and 102.3+/-54.99 respectively. On the electron microscopic study, the size of zymogen granule in the gastric chief cells of normal control, tumor control and AG60-treated groups were 0.74+/-0.208 micrometer, 1.18+/-0.291 micrometer and 0.97+/-0.259 micrometer, respectively. And the mitochondrial size of the gastric chief cells of normal control, tumor control and AG60-treated groups were 0.86+/-0.364 micrometer, 1.02+/-0.466 micrometer and 0.92+/-0.390 micrometer, respectively. And in the AG60 treated group, most chief cells did not show any difference in ultrastructure, except that myelin figures were more frequently observed, in comparison with that of nornmal control group. From the above results, AG60 may suppress the DNA synthesis of the gastric epithelial cells, but does not results severe fine structural defect on the gastric chief cells. These results suggest that AG60 is expected as one of the most effective anticancer drugs.

Ultrastructural Alterations in the Gastric Chief Cells of Mouse, induced by 5-Fluorouracil or Mitomycin C / 대한해부학회지

This experiment was performed to evaluate the morphological responses of the gastric chief cells of the mouse, inoculated with Ehrlich carcinoma cells in the inguinal area, following administration of 5-fluorouracil or mitomycin C. Healthy adult ICR mice weighing 25 gm each were divided into normal and experimental groups (experimental control group, 5-fluorouracil-treated group and mitomycin C-treated group). In the experimental group, 1x107 Ehrlich carcinoma cells were inoculated subcutaneously in the inguinal area. From next day after inoculations, 0.2mL of saline (experimental control group), 5-fluorouracil (30 mg/kg, 5-fluorouracil-treated group), or mitomycin C (400 microg/kg, mitomycin C-treated group) were injected subcutaneously to the animals every other day, respectively. The day following the 7th injection, animals were sacrificed. Pieces of the tissue were taken from the gastric mucosa, prefixed with 2.5% glutaraldehyde-1.5% paraformaldehyde solution, followed by post-fixation with 1% osmium tetroxide solution. The ultrathin sections were stained with uranyl acetate and lead citrate. The size of zymogen granule and the size of the mitochondrion in the gastric chief cells were observed and compared. In the 5-fluorouracil treated group, most chief cells did not show any difference in ultrastructure, except myelin figures were more frequently observed, in comparison with those of normal control group. But in the mitomycin Ctreated group, necrotic cells were more frequently observed than in normal control and 5-fluorouracil-treated group. The size of zymogen granule in the gastric chief cells of normal control, experimental control, 5-fluorouracil-treated and mitomycin C-treated groups were 0.98 (+/-0.108)microm, 1.05 (+/-0.092)microm, 0.94 (/-0.123)microm and 0.93 (+/-0.156)microm, respectively. And the size of mitochondrion in the gastric chief cells of normal control, experimental control, 5-fluorouracil-treated and mitomycin C-treated groups were 0.80 (+/-0.130)microm, 0.83 (+/-0.143)microm, 0.87 (+/-0.165)microm and 0.81 (+/-0.083)microm, respectively. From the above results, in the treatment of low therapeutic doses of anticancer drugs into the animals inoculated with Ehrlich carcinoma cells, 5-fluorouracil may not suppress function of the gastric chief cells, but mitomycin C may exert a vicious influence on the function of the gastric chief cells.