Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis

Ludovica F. Buttó, Adam Pelletier, Shyam K. More, Nan Zhao, Abdullah Osme, Christopher L. Hager, Mahmoud A. Ghannoum, Rafick Pierre Sekaly, Fabio Cominelli, Maneesh Dave

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Intestinal epithelial barrier dysfunction is a risk factor in the pathogenesis of Crohn's disease (CD); however, no corrective FDA-approved therapies exist. We used an enteroid (EnO)-based system in two murine models of experimental CD, SAMP1/YitFc (SAMP) and TNFΔARE/+ (TNF). While severely inflamed SAMP mice do not generate EnOs, “inflammation-free” SAMP mice form EnO structures with impaired morphology and reduced intestinal stem cell (ISC) and Paneth cell viability. We validated these findings in TNF mice concluding that inflammation in intestinal tissues impedes EnO generation and suppressing inflammation by steroid administration partially rescues impaired formation in SAMP mice. We generated the first high-resolution transcriptional profile of the SAMP ISC niche demonstrating that alterations in multiple key pathways contribute to niche defect and targeting them may partially rescue the phenotype. Furthermore, we correlated the defects in formation and the rescue of EnO formation to reduced viability of ISCs and Paneth cells.

Original languageEnglish (US)
Pages (from-to)389-407
Number of pages19
JournalStem Cell Reports
Volume15
Issue number2
DOIs
StatePublished - Aug 11 2020

Keywords

  • Crohn's disease
  • enteroids
  • epithelial barrier defect
  • intestinal stem cell niche
  • organoids
  • Paneth cells
  • RNAseq
  • SAMP1/YitFc
  • stem cells
  • TNF

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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