Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here we show the persistence of Lgr5+ cells in oxazolone, TNBS, and Il10-/- and Il10-/- Tnfr1-/- IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function.
Junctional complexes that mediate cell adhesion are key to epithelial integrity, cell division and permeability barrier formation. In Drosophila, the scaffolding proteins Scribble (Scrib) and Discs Large (Dlg) are key regulators of epithelial polarity, proliferation, assembly of junctions and protein trafficking. We found that Scrib and Dlg are necessary for the formation of the tricellular junction (TCJ), a unique junction that forms in epithelia at the point of convergence of three neighboring cells. Scrib and Dlg are in close proximity with the TCJ proteins Gliotactin (Gli) and Bark Beetle (Bark), and both are required for TCJ protein recruitment. Loss of Bark or Gli led to basolateral spread of the TCJ complex at the cell corners. Loss of the septate junction proteins Nrx-IV and the Na + /K + ATPase also resulted in basolateral spread of the entire TCJ complex at the cell corners. The Scrib PDZ1-2 domains and the Dlg GUK domain are necessary for Bark and Gli localization to the TCJ. Overall, we propose a model in which Scrib and Dlg are key components of the TCJ, and form a complex with Bark and Gli.
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