Abstract
Enhancement of Wnt signaling is fundamental for stem cell function during intestinal regeneration. Molecular modules control Wnt activity by regulating signal transduction. CD44 is such a positive regulator and a Wnt target gene. While highly expressed in intestinal crypts and used as a stem cell marker, its role during intestinal homeostasis and regeneration remains unknown. Here we propose a CD44 positive-feedback loop that boosts Wnt signal transduction, thus impacting intestinal regeneration. Excision of Cd44 in Cd44fl/fl;VillinCreERT2 mice reduced Wnt target gene expression in intestinal crypts and affected stem cell functionality in organoids. Although the integrity of the intestinal epithelium was conserved in mice lacking CD44, they were hypersensitive to dextran sulfate sodium, and showed more severe inflammation and delayed regeneration. We localized the molecular function of CD44 at the Wnt signalosome, and identified novel DVL/CD44 and AXIN/CD44 complexes. CD44 thus promotes optimal Wnt signaling during intestinal regeneration.
Highlights
The fast self-renewal of the intestinal epithelium is carried out by intestinal stem cells (ISCs) that lie at the bottom of the intestinal crypts and express leucine-rich repeat G-protein coupled receptor 5 (Lgr5)
The same observations could be made in the Cd44fl/fl;VillinCreERT2 mice not treated with tamoxifen used as an additional control (Supplementary Fig. 1Bc/c’, Bg/g’)
In the Cd44Δie mice, CD44 was exclusively removed from the crypts, organoids are dependent on the activity of the Wnt pathway as well as on a functional interplay between Lgr5+ stem cells and Paneth cells (PCs) [17, 18]
Summary
The fast self-renewal of the intestinal epithelium is carried out by intestinal stem cells (ISCs) that lie at the bottom of the intestinal crypts and express leucine-rich repeat G-protein coupled receptor 5 (Lgr). The fast self-renewal of the intestinal epithelium is carried out by intestinal stem cells (ISCs) that lie at the bottom of the intestinal crypts and express leucine-rich repeat G-protein coupled receptor 5 (Lgr5) These cells give rise to transit-amplifying (TAs) cells that differentiate into enterocytes or secretory lineages like enteroendocrine cells (EECs), goblet cells (GCs), and Paneth cells (PCs) [1]. The activity of Wnt is the highest in the intestinal stem cell niche at the bottom of the crypts, where it acts as the major regulator of ISC self-renewal and differentiation, and decreases in a gradient along the crypt–villus axis [1, 4]. Upon Wnt ligand binding to FZD and LRP6, a multiprotein signaling complex—the Wnt signalosome—is assembled at the membrane, immobilizing the β-catenin destruction complex. β-catenin translocates to the nucleus activating the TCF/LEF-mediated Wnt transcriptional program [9]
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