Atrophic gastritis (parietal cell loss or oxyntic atrophy) is considered the most common precursor to gastric cancer in humans. Chronic infection with Helicobacter pylori represents the most common cause of atrophy. In the stomach, metaplasia arises following parietal cell loss. Two types of metaplasia occur in he human stomach: intestinal metaplasia (the presence of intestinal goblet cell lineages in the stomach) and Spasmolytic Polypeptide-Expressing Metaplasia or SPEM (the presence of deep antral gland type mucus cells in the stomach corpus). Investigations over the past decade have led to the recognition that SPEM lineages are substantially derived from transdifferentiation of protein-secreting chief cells into mucus-secreting metaplastic lineages. SPEM represents an initial metaplastic response to acute injuries in the stomach. However, progression of SPEM to more intestinalized and proliferative lineages requires the influence of M2- macrophages. With chronic inflammation in the stomach, SPEM appears to evolve into intestinal metaplasia. Our recent investigations have also determined that activation of Ras is critical at all stages of metaplasia evolution from initial transdifferentiation of SPEM, to promotion of proliferative SPEM, and to emergence of intestinal metaplasia. Thus, critical extrinsic immune factors and intrinsic epithelial Ras signaling combine to promote the evolution and expansion of metaplasia in the stomach. We have therefore hypothesized that immune cell populations drive both the induction of SPEM and the progression of metaplasia. To evaluate this hypothesis, we will examine two specific aims: First, we will examine the role of intrinsic immune cells (ILC2s) in the gastric mucosa on the induction of metaplasia. Our previous investigations have implicated a cascade of IL-33 to IL-13 in the induction of metaplasia in the corpus of the stomach. Since intrinsic immune ILC2s are thought to represent the major population of cells responsible for secretion of IL-13, we will seek to characterize the diversity of ILC2s in the stomach and their response to parietal cell loss. We will examine whether ablation of ILC2s prevents the induction of metaplasia following acute oxyntic atrophy. Finally we will examine whether IL-13 is a direct activator of transdifferentiation in chief cells. Second, will identify the immune cell derived factors and intrinsic autocrine epithelial signals that can promote progression of metaplasia to a more intestinalized and proliferative phenotype. While transdifferentiation of chief cells into SPEM is an initial transition triggered as a response to parietal cell loss, further progression to more proliferative and intestinalized metaplasia requires other influences. We have developed metaplastic gastroid lines from Mist1-KRas mice 1 month or 4 months after induction of active Ras, which display the characteristics of either SPEM or intestinal metaplasia, respectively. We will utilize these cells to evaluate whether immune or autocrine regulators can influence SPEM to progress towards intestinal metaplasia. These investigations will define more precisely the dynamic regulators of the induction and progression of metaplasia in the stomach.
Metaplasia evolves in the stomach following loss of acid secreting parietal cells through protein secreting chief cells transdifferentiating into mucus secreting cells. This proposal seeks to understand how immune cells intrinsic to the stomach mucosa mediate induction of metaplasia and how intrinsic immune cells and macrophages promote the progression of metaplasia into a more proliferative and intestinalized phenotype.
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| Goldenring, James R (2018) Pyloric metaplasia, pseudopyloric metaplasia, ulcer-associated cell lineage and spasmolytic polypeptide-expressing metaplasia: reparative lineages in the gastrointestinal mucosa. J Pathol 245:132-137 |
| Petersen, Christine P; Meyer, Anne R; De Salvo, Carlo et al. (2018) A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut 67:805-817 |
| Yang, Qing; Yasuda, Tomohiko; Choi, Eunyoung et al. (2018) MEK Inhibitor Reverses Metaplasia and Allows Re-Emergence of Normal Lineages in Helicobacter pylori-Infected Gerbils. Gastroenterology : |
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| Goldenring, James R; Mills, Jason C (2017) Isthmus Time Is Here: Runx1 Identifies Mucosal Stem Cells in the Gastric Corpus. Gastroenterology 152:16-19 |
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| Petersen, Christine P; Mills, Jason C; Goldenring, James R (2017) Murine Models of Gastric Corpus Preneoplasia. Cell Mol Gastroenterol Hepatol 3:11-26 |
| Burclaff, Joseph; Osaki, Luciana H; Liu, Dengqun et al. (2017) Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach. Gastroenterology 152:762-766.e7 |
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