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

Authors :
Fabio Cominelli
Maneesh Dave
Mahmoud A. Ghannoum
Christopher Hager
Nan Zhao
Ludovica F. Buttó
Shyam K. More
Abdullah Osme
Rafick Pierre Sekaly
Adam Pelletier
Source :
Stem cell reports, vol 15, iss 2, Stem Cell Reports
Publication Year :
2020
Publisher :
eScholarship, University of California, 2020.

Abstract

Summary 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.<br />Graphical Abstract<br />Highlights • Enteroid (EnO) formation is impaired in inflammation-free SAMP mice • SAMP EnOs maintain impaired functions ex vivo recapitulating epithelial CD defect • Inflammation impedes EnO formation, which is partially restored by steroid treatment • Reduced number of viable intestinal stem and Paneth cells correlate with EnO defect<br />In this article, Dave and Cominelli and colleagues show that early alterations in key pathways and cytokines results in impaired enteroid (EnO) formation in two murine models of experimental Crohn’s disease, SAMP1/YitFc (SAMP) and TNFΔARE/+ (TNF). While severely inflamed SAMP and TNF mice do not generate EnOs, SAMP mice before disease onset form EnO structures with impaired morphology and reduced intestinal stem cell and Paneth cell viability.

Details

Database :
OpenAIRE
Journal :
Stem cell reports, vol 15, iss 2, Stem Cell Reports
Accession number :
edsair.doi.dedup.....facee457900722467a4fed3c6173eb6c