The antral gland

The antral glands are mainly characterized by mucus-producing cells and hormone-producing endocrine cells which originate from adult stem cells.

1.1.1.1. The stem cell compartment

In the murine antrum stem cells are located in the gland base and are responsible for the self-renewal and repopulation of the entire gland and all resident cell lineages in a monoclonal fashion (Vries, Huch, and Clevers 2010). For a long time, the specific marker of antral stem cells was unknown. In the small intestine which is adjacent to the antrum, Lgr5 was found to be the specific marker for intestinal stem cells. With the help of Lgr5^{EGFP‐ires‐CreERT2}/Rosa26R‐LacZ reporter mice, lineage tracing experiments were conducted. In these mice, Cre recombinase was activated after tamoxifen administration leading to lacZ labeling of Lgr5 expressing cells. Through this approach evidence was given that in mice all intestinal cell types within a crypt originate from the Lgr5 positive, LacZ labeled stem cell in the crypt base (Barker et al. 2007). Extensive investigations in the antrum using the same approach have revealed that three to four cells in the base of the gland express Lgr5 and thus were determined as stem cells by lineage tracing, giving rise to all cell lineages (Barker et al. 2010; Leushacke et al.

2013). Another quiescent stem cell population was described by Qiao et al. (2007) which is located in the isthmus of antral glands and is activated by inflammatory

1.1 The human gastric mucosa

stimuli. The authors showed that upon interferon γ (IFNγ) stimulation these stem cells start to divide and regenerate the entire gland. The lineage tracing experiments by Barker et al. (2010) identifying Lgr5 to be the stem cell marker instead showed that quiescent stem cells in the isthmus also initially originate from the Lgr5 stem cells in the base. After the stem cell marker was identified further investigations were made on the characterization of the stem cell niche and its homeostasis. Thus, it was reported that Notch signaling is essential for the homeostasis of Lgr5+ antral stem cells as pathway inhibition decreased the proliferation of the stem cells and progenitor cells (Demitrack et al. 2015). Moreover, Lgr5 is a target gene of the Wnt/β-Catenin pathway, thus the stem cell niche in the intestine and consequently also in the antrum highly depends on the presence of WNT as fuel for Lgr5 expression to maintain the stemness (Vries, Huch, and Clevers 2010). In addition to Lgr5, Sigal et al. (2017) showed that in the murine antrum a further stem cell compartment exists which is Axin2 positive and is located right above the Lgr5+ stem cells. This second stem cell population is as well able to repopulate the antral gland.

1.1.1.2. Mucus producing cells

The pit region is populated by mucus-producing pit cells or foveolar cells which secrete surface mucus dominated by the mucin 5AC (MUC5AC). The transcription factor FOXQ1 regulates MUC5AC expression in pit cells (Verzi et al. 2008). Foveolar cells are terminally differentiated and short-living with a turnover of three days, developing through constant migration from the stem cell compartment and shed into the lumen when they reach the outer surface (Kim and Shivdasani 2016). Moreover, foveolar cells express Trefoil factor (TFF) 1 which can be used as a cell-specific marker as TFF1 is only expressed in foveolar cells (Karam, Tomasetto, and Rio 2004). The differentiation of the cells into foveolar is regulated by the Wnt/-Catenin signaling pathway. In vitro experiments using organoids have shown that constant supplementation with WNT and RSPO maintains the stemness and longevity of the organoid culture while the removal of both factors induced foveolar differentiation in antral organoids marked by MUC5AC expression (Schlaermann et al. 2014; Bartfeld et al. 2015). Moreover, in mice, it was shown that BMP2, which might originate from mesenchymal cells, has also

1.1 The human gastric mucosa

Other mucus-producing cells are located deeper in the antral gland. These mucus gland cells secrete acidic mucus enriched in mucin 6 (MUC6) that covers the epithelial cells from the base to the sub-foveolar region (De Bolos, Garrido, and Real 1995; Bartman et al. 1998). Furthermore, mucus gland cells co-express TFF2 also known as spasmolytic polypeptide. TFF2 is a further mucus gland cell specific marker as it is only expressed in MUC6 positive cells (Hanby et al. 1993).

1.1.1.3. Endocrine cells

The antral gland is also populated by hormone-secreting endocrine cells which are distributed among the non-endocrine cells. Two different types of endocrine cells with important function are present in the antrum: (1) G-cells secrete gastrin which is a specific marker for the antrum as these cells are only to be found in the antrum (Choi et al. 2014). G-cells are so-called “open” endocrine cells as the activation is due to luminal content. The gastrin release is triggered by proteins, amino acids and amines in the lumen and gastrin, in turn, activates the gastric acid secretion of parietal cells in the gastric corpus. (2) D-cells are as well “open” endocrine cells producing somatostatin which inhibits locally the gastrin secretion in G-cells. The somatostatin secretion is activated by gastric acid from the corpus and functions as a negative-feedback regulation to control the gastrin release. Somatostatin producing D-cells are also to be found in the corpus but seem to have different functions in the two compartments (Vassallo, Capella, and Solcia 1971; Dockray, Varro, and Dimaline 1996; Latorre et al.

2016). Chromogranin A is a further hormone that is widely expressed in the gastrointestinal tract including the stomach, pancreas, and intestine. The expression is not restricted to a specific cell type and can be found for example in G-cells in the antrum (Dockray, Varro, and Dimaline 1996; Portela-Gomes and Stridsberg 2002).

1.1 The human gastric mucosa