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Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis
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 TNF(ΔARE/+) (TNF). While severely inflam...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419719/ https://www.ncbi.nlm.nih.gov/pubmed/32679063 http://dx.doi.org/10.1016/j.stemcr.2020.06.017 |
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author | Buttó, Ludovica F. Pelletier, Adam More, Shyam K. Zhao, Nan Osme, Abdullah Hager, Christopher L. Ghannoum, Mahmoud A. Sekaly, Rafick-Pierre Cominelli, Fabio Dave, Maneesh |
author_facet | Buttó, Ludovica F. Pelletier, Adam More, Shyam K. Zhao, Nan Osme, Abdullah Hager, Christopher L. Ghannoum, Mahmoud A. Sekaly, Rafick-Pierre Cominelli, Fabio Dave, Maneesh |
author_sort | Buttó, Ludovica F. |
collection | PubMed |
description | 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 TNF(ΔARE/+) (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. |
format | Online Article Text |
id | pubmed-7419719 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-74197192020-08-14 Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis Buttó, Ludovica F. Pelletier, Adam More, Shyam K. Zhao, Nan Osme, Abdullah Hager, Christopher L. Ghannoum, Mahmoud A. Sekaly, Rafick-Pierre Cominelli, Fabio Dave, Maneesh Stem Cell Reports Article 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 TNF(ΔARE/+) (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. Elsevier 2020-07-16 /pmc/articles/PMC7419719/ /pubmed/32679063 http://dx.doi.org/10.1016/j.stemcr.2020.06.017 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Buttó, Ludovica F. Pelletier, Adam More, Shyam K. Zhao, Nan Osme, Abdullah Hager, Christopher L. Ghannoum, Mahmoud A. Sekaly, Rafick-Pierre Cominelli, Fabio Dave, Maneesh Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis |
title | Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis |
title_full | Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis |
title_fullStr | Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis |
title_full_unstemmed | Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis |
title_short | Intestinal Stem Cell Niche Defects Result in Impaired 3D Organoid Formation in Mouse Models of Crohn's Disease-like Ileitis |
title_sort | intestinal stem cell niche defects result in impaired 3d organoid formation in mouse models of crohn's disease-like ileitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419719/ https://www.ncbi.nlm.nih.gov/pubmed/32679063 http://dx.doi.org/10.1016/j.stemcr.2020.06.017 |
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