| 抄録 |
Helicobacter pylori infection in humans causes prominent chronic inflammation and oxyntic atrophy, leading to two distinct types of metaplasia：intestinal metaplasia（IM）and spasmolytic polypeptide expressing metaplasia（SPEM）. Using lineage-mapping studies in mice, we have demonstrated that parietal cell loss results in the transdifferentiation of chief cells into SPEM cells. These studies indicated that pre-neoplastic metaplasias arise from transdifferentiation of mature chief cells rather than aberrant differentiation of normal mucosal stem cells. Increasing data suggest that IM arises from SPEM in humans. We have now examined the role of inflammatory cell populations in induction of SPEM using the L635 model of acute oxyntic atrophy associated with severe inflammation. Rag1 and INFγ knock out mice treated with L635 develop SPEM as in wild type mice, suggesting that T-cells and B-cells are not necessary for the development of acute proliferative SPEM. Similarly, depletion of neutrophils with anti-Ly6G antibodies did not alter the development of SPEM after L635 treatment. In contrast, depletion of macrophages with clodronate treatment markedly ameliorated the induction of SPEM by L635 without changing the induction of parietal cell loss. Further studies have defined that M2-polarized macrophages are critical drivers of the induction of SPEM. Finally, recent investigations have noted that activation of Ras may be associated with over a third of human gastric cancers. We therefore examined the effects of targeted inducible expression of activated Ras（RasG12D）in Mist1-expressing mature chief cells. Expression of activated Ras in chief cells leads to transdifferentiation of chief cells into SPEM within 2-4 weeks of induction. By 6-8 weeks after Ras induction, SPEM cells derived from chief cells further differentiate into MUC2-expressing goblet cells. By 16 weeks after induction, invasive and dysplastic lesions are present in the stomach. These studies indicate that activation of Ras is a critical driver of the trasndifferentiation of chief cells into SPEM and the further evolution of SPEM into IM. |
