BASIC AND TRANSLATIONAL ATcapabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE− mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE− mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori. In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.

The intestinal epithelium does not function in isolation, but interacts with many components including the Enteric Nervous System (ENS). Understanding ENS and intestinal epithelium interactions requires multidisciplinary approaches to uncover cells involved, mechanisms used, and the ultimate influence on intestinal physiology. This review is intended to serve as a reference for epithelial biologists interested in studying these interactions. With this in mind, this review aims to summarize the basic anatomy of the epithelium and ENS, mechanisms by which they interact, and techniques used to study these interactions. We highlight in vitro, ex vivo and in vivo techniques. Additionally, ENS influence on epithelial proliferation and gene expression within stem and differentiated cells as well as gastrointestinal cancer are discussed.

The colonic epithelium harbors a complex network of adult stem cells that integrate signals from many supporting cells to assist in their decision making. In this study, we ablate an epithelial secretory support cell population characterized by Reg4 expression, to investigate the systemic impact on stemness-related cell signaling pathways. Ablation of these cells results in a hyperproliferative state as well as paradoxical activation of Notch signaling, with the proliferative effect continuing even during Notch inhibition. Reg4+ cell ablation also causes an unexpected remodeling of the mesenchyme. We observe increased presence of Pdgfra-high fibroblasts and an expanded network of smooth muscle myofibroblasts, suggesting that Reg4-ablation reorganizes signaling between epithelium and mesenchyme. These changes occur in the absence of any significant immunological inflammatory response. Our data demonstrate that Reg4+ cells are critical directors of homeostatic epithelial-mesenchymal signaling. Further, this ablation model is an in vivo system for probing cell-cell interactions in the colonic stem cell niche.

The cellular census of the colonic crypt is tightly regulated, yet the molecular mechanisms that regulate this census are not fully understood. Lrig3, a transmembrane protein, is expressed in colonic crypt epithelial cells, including the stem, progenitor, and differentiated cell types. Mice missing Lrig3 have a disruption in their cellular census: using a novel Lrig3-/- mouse we demonstrate that Lrig3-/- mice have more cells per crypt, a greater mucosal area, and longer colons compared to wildtype mice, suggesting the expression of Lrig3 is required for both the total number of epithelial cells in the mouse colon, as well as colon length. In addition, we show Lrig3-/- mice have significantly more stem, progenitor, and deep crypt secretory cells, yet harbor a normal complement of enteroendocrine, Tuft, and absorptive cells. Lrig3-/- mice also have a concomitant decrease in phosphorylated Extracellular signal-related kinases, indicating the loss of Lrig3 leads to an expansion of the colonic stem cell compartment, in an Erk-dependent manner. Our study describes the expression of Lrig3 within the colon, defines perturbations in mice lacking Lrig3, and supports a role for Lrig3 in the establishment of both colonic crypt structure and cellular census, defined as the epithelial cell type and number in colon crypts.