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COMPARATIVE SINGLE CELL PROFILING OF MUCOSA AND ORGANOIDS IMPLICATES ALTERED EPITHELIAL-MESENCHYMAL INTERACTIONS MEDIATED BY PTGER4 IN PERIANAL FISTULIZING CROHN’S DISEASE

ABSTRACT: Background and aims: Perianal fistulizing Crohn’s disease (CD) is severe and often more difficult to treat than luminal CD. Current therapeutics focusing solely on the immune system neither target epithelial and mesenchymal compartments nor consider genetic/epigenetic mechanisms, potentially missing causative aspects of the disease. Thus, the mucosal cells and organoids from a cohort of perianal fistulizing CD patients and controls with diverse genetic backgrounds were experimentally examined. Results: Overall, 140,503 mucosa and 77,044 organoid cells were sequenced. Inflamed perianal CD showed changes across the mucosal compartments (epithelium, immune, stromal), the most dramatic taking place in the epithelium. Epithelial changes occurring in the rectum of perianal CD patients associated with inflammation, gender, and ancestry, and were accompanied by a reduction in differentiated lineages. Organoids from the patient cohort retained both the gender- and ancestral-specific gene expression but did not overwhelmingly reflect their disease status. Organoids lacked bona fide differentiated lineages, but secretory pathways were promoted through PGE2-PTGER4 signaling and HDAC function. Conclusion: Epigenetic modifications are disrupted in the epithelium during inflammation and perianal fistulizing CD that affect the differentiation capacity of those cells, limiting their production/function and thus diminishing the ability of the patients’ mucosal tissue to heal. These epigenetic modifications appear to be modulated by crosstalk between the epithelial and mesenchymal cells, and thus might be leveraged therapeutically.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256497 | GEO | 2024/11/22

REPOSITORIES: GEO

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Project description:Human intestinal epithelial organoids (IEO) culture models are rapidly emerging as novel experimental tools to investigate fundamental aspects of intestinal epithelial (patho)physiology. Cellular source and culture protocols vary between different IEO models and reliable markers for their characterization/validation are currently limited. DNA methylation has been demonstrated to play a key role in regulating gene expression and cellular function. This epigenetic mark is comparably stable and has been shown to reflect cellular identity such as tissue origin, developmental stage and age. Our genome wide DNA methylation datasets of purified human epithelium represent a unique resource, which can be used by other researchers to validate their model systems We provide the following datasets of genome-wide DNA methylation profiling by Infinium HumanMethylation450 BeadChip: Purified intestinal epithelial cells (EpCAM+) from paediatric ileum and colon, Non-epithelial mucosal cells (EpCAM-), Whole colonic mucosal biopsies, Intestinal organoid cultures from paediatric ileum and colon, Purified intestinal epithelial cells (EpCAM+) from foetal small intestine and foetal large intestine, Intestinal organoid cultures from foetal small intestine and foetal large intestine, Intestinal organoid cultures derived from induced pluripotent stem cells. Note: Some samples in this data set were previously submitted to ArrayExpress under accession number E-MTAB-3709. They're clearly marked in the âDescriptionâ field in sample annotations. Information about batch effect during sample handling is included in the experimental variable âblockâ. Batch effect is not massive but present, so it is recommended that batch correction is carried out in data analysis. Complementary RNA-seq data on the purified cells and organoids can be found in ArrayExpress at E-MTAB-5015 ( https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-5015/ ).

Dataset Information

COMPARATIVE SINGLE CELL PROFILING OF MUCOSA AND ORGANOIDS IMPLICATES ALTERED EPITHELIAL-MESENCHYMAL INTERACTIONS MEDIATED BY PTGER4 IN PERIANAL FISTULIZING CROHN’S DISEASE

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