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Abstract
Objective UC is a chronic inflammatory disease of the colonic mucosa. Growing evidence supports a role for epithelial cell defects in driving pathology. Moreover, long-lasting changes in the epithelial barrier have been reported in quiescent UC. Our aim was to investigate whether epithelial cell defects could originate from changes in the epithelial compartment imprinted by the disease.
Design Epithelial organoid cultures (EpOCs) were expanded ex vivo from the intestinal crypts of non-IBD controls and patients with UC. EpOCs were induced to differentiate (d-EpOCs), and the total RNA was extracted for microarray and quantitative real-time PCR (qPCR) analyses. Whole intestinal samples were used to determine mRNA expression by qPCR, or protein localisation by immunostaining.
Results EpOCs from patients with UC maintained self-renewal potential and the capability to give rise to differentiated epithelial cell lineages comparable with control EpOCs. Nonetheless, a group of genes was differentially regulated in the EpOCs and d-EpOCs of patients with UC, including genes associated with antimicrobial defence (ie, LYZ, PLA2G2A), with secretory (ie, ZG16, CLCA1) and absorptive (ie, AQP8, MUC12) functions, and with a gastric phenotype (ie, ANXA10, CLDN18 and LYZ). A high rate of concordance was found in the expression profiles of the organoid cultures and whole colonic tissues from patients with UC.
Conclusions Permanent changes in the colonic epithelium of patients with UC could be promoted by alterations imprinted in the stem cell compartment. These changes may contribute to perpetuation of the disease.
- INTESTINAL EPITHELIUM
- GENE EXPRESSION
- STEM CELLS
- ULCERATIVE COLITIS
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Footnotes
Contributors ID designed and conducted experiments, acquired and analysed data, and wrote the manuscript. RM-B, EF-P and RFL designed and conducted experiments. NP executed bioinformatics and biostatistics analysis. MCM, JMdC, JL, IO and JP recruited patients and/or collected samples. PJ and EB designed and supervised experiments. AS designed the study, supervised experiments, analysed data and wrote the manuscript.
Funding This work was supported by grants BFU2012-35999/BFI, MC1_TV3_122931, PIE13/00033 and the Helmsley Trust. RM-B. was a recipient of an FPI fellowship from the Ministerio de Economía y Competitividad (BES-2010-030033). EF-P was a recipient of an FI-DGR 2015 fellowship from AGAUR (Generalitat de Catalunya). RFL was supported by a research fellowship from CAPES-Brazil. This work is cofinanced by the European Union through the European Regional Development Fund (ERDF), ‘A way of making Europe’. NP is supported by the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Hospital Clínic and Sant Joan de Deu Ethical Committees, Barcelona, Spain.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The transcriptional data of the EpOCs and d-EpOCs generated from non-IBD controls and patients with UC have been deposited in the Gene Expression Omnibus at the National Center for Biotechnology Information (NCBI) with accession no. GSE75916.
Writing assistance English language assistance by Joe Moore was funded by the Leona and Harry Helmsley Charitable Trust.