Article1 min read·Published Apr 2019Older

Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis

Part of Inflammatory & Immune-Mediated GI Disease 9 items

pubmed.ncbi.nlm.nih.gov

Michael Helmrath

Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain C. difficile, Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell (IESC) regeneration. However, how IESCs are sustained to specify Paneth-like cells as their niche remains unclear. Cytokine-JAK-STATs are required for IESC regeneration. We investigated how constitutive STAT5 activation (Ca-pYSTAT5) restricts IESC differentiation towards niche cells to restrain C. difficile infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on C. difficile colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis. In contrast, Ca-pYSTAT5 enhanced Paneth cell lineage tracing and restricted Lgr5 IESC differentiation towards pYSTAT5+Lgr5-CD24+Lyso+ or cKit+ niche cells, which imprinted Lgr5hiKi67+ IESCs. Mechanistically, pYSTAT5 activated Wnt/β-catenin signaling to determine Paneth cell fate. In conclusion, Ca-pYSTAT5 gradients control niche differentiation. Lack of pYSTAT5 reduces the niche cells to sustain IESC regeneration and induces C. difficile ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.

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Article · Apr 2019 · 1 min read

In brief

This study demonstrates that constitutive STAT5 activation controls Paneth cell differentiation and maintains the intestinal stem cell niche, protecting against C. difficile colitis. STAT5 deficiency reduces Paneth cells and increases susceptibility to infection, while activated STAT5 enhances niche cell populations through Wnt/β-catenin signaling.

Written by the GCMD Library team from the article.

Michael Helmrath

Statements in this article

Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis.
Established
Paneth cells secrete bactericidal products to restrain C. difficile.
Established
Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell regeneration.
Established
STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis.
Research
Constitutive STAT5 activation enhanced Paneth cell lineage tracing and restricted Lgr5 intestinal epithelial stem cell differentiation towards pYSTAT5+Lgr5-CD24+Lyso+ or cKit+ niche cells.
Research
pYSTAT5+Lgr5-CD24+Lyso+ or cKit+ niche cells imprinted Lgr5hiKi67+ intestinal epithelial stem cells.
Research
pYSTAT5 activated Wnt/β-catenin signaling to determine Paneth cell fate.
Research
Constitutive STAT5 activation gradients control niche differentiation.
Research
Lack of pYSTAT5 reduces the niche cells to sustain intestinal epithelial stem cell regeneration and induces C. difficile ileocolitis.
Research
STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.
Research