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

Life Sci Alliance. 2019 Apr 4;2(2):e201900296. doi: 10.26508/lsa.201900296. Print 2019 Apr.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • Clostridioides difficile*
  • Colitis / metabolism*
  • Colitis / microbiology*
  • Disease Models, Animal
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Organoids / metabolism
  • Organoids / microbiology
  • Paneth Cells / metabolism*
  • Paneth Cells / microbiology*
  • STAT5 Transcription Factor / metabolism*
  • Stem Cell Niche / physiology
  • Tumor Suppressor Proteins / metabolism*
  • Wnt Signaling Pathway
  • beta Catenin / metabolism


  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Stat5a protein, mouse
  • Tumor Suppressor Proteins
  • beta Catenin