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Updated: Jun 3, 2026
Studying the Epithelial Effects of Intestinal Inflammation In Vitro on Established Murine Colonoids
Published on: June 2, 2023
The Wnt antagonist Dkk1 regulates intestinal epithelial homeostasis and wound repair
Stefan Koch1, Porfirio Nava, Caroline Addis
1Epithelial Pathobiology Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA.
Background & Aims:
Dkk1 is a secreted antagonist of the Wnt/β-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine.
Methods:
We used doubleridge mice (Dkk1d/d), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/β-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2'-deoxyuridine incorporation, and immunostaining.
Results:
Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of β-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/d mice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/β-catenin, ERK/Elk-1, and c-Jun pathways.
Conclusions:
Dkk1, an antagonist of Wnt/β-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.
Insights
Inhibition of Dkk1, a Wnt/β-catenin antagonist, promotes intestinal epithelial cell proliferation and accelerates wound repair after colitis. Reduced Dkk1 enhances crypt regeneration but can lead to architectural irregularities.
Area of Science:
- Gastroenterology
- Molecular Biology
- Cell Biology
Background:
- Dickkopf-1 (Dkk1) is a secreted antagonist of the Wnt/β-catenin pathway.
- Dkk1 is induced by inflammatory cytokines during colitis, exacerbating tissue damage via epithelial cell apoptosis.
- The physiological role of Dkk1 in normal intestinal homeostasis and wound repair remains largely unknown.
Purpose of the Study:
- To investigate the role of Dkk1 in intestinal epithelial homeostasis and wound repair.
- To determine the effects of Dkk1 inhibition on adult intestinal morphology and function.
Main Methods:
- Utilized doubleridge mice (Dkk1d/d) with reduced Dkk1 expression and an inhibitory Dkk1 antibody.
- Induced intestinal inflammation using dextran sulfate sodium (DSS) followed by a recovery period.
- Assessed epithelial homeostasis and signaling pathway activity through morphometric analysis, bromo-2'-deoxyuridine incorporation, and immunostaining.
Main Results:
- Reduced Dkk1 expression led to increased epithelial cell proliferation and crypt lengthening in the large intestine, associated with enhanced β-catenin activity.
- Dkk1 inhibition during acute colitis resulted in faster recovery from inflammation but caused crypt architectural irregularities and epithelial hyperproliferation.
- Survival signaling pathways, including AKT/β-catenin, ERK/Elk-1, and c-Jun, were upregulated in Dkk1-deficient mice.
Conclusions:
- Dkk1 plays a crucial role in regulating intestinal epithelial homeostasis under both physiological and inflammatory conditions.
- Dkk1 antagonism stimulates a potent proliferative response, significantly promoting wound repair following colitis.
- Targeting Dkk1 may offer therapeutic potential for enhancing intestinal recovery after inflammatory injury.
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