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

Stem Cell Reports
Ludovica F ButtòManeesh Dave

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.

Citations

Nov 12, 2020·Cell Proliferation·Erpeng Yang, Jun Shen
Jan 17, 2021·Viruses·Georges TarrisGaël Belliot

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Datasets Mentioned

BETA
GSE124825

Methods Mentioned

BETA
flow cytometry
laser capture microscopy
RNA-seq
IECs
scanning electron microscopy
PCR

Software Mentioned

GSEA
Nanostring
EnO
GraphPad
ImageJ
GraphPad Prism

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