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Single-Cell Transcriptome Study Links Gut Development, Pediatric Crohn's Disease

NEW YORK – Pediatric Crohn's disease appears to involve altered connections between intestinal cells and the reactivation of regulatory features found in developing gut cells, according to findings from a single-cell RNA sequencing study that analyzed human intestine samples, fetal intestinal organoids, and samples from children with or without the inflammatory bowel disease (IBD). 

"[O]ur results confirm previous reports of altered intestinal epithelial cell dynamics in regenerating [Crohn's disease] epithelium and identify several disease-associated cell-cell interactions in childhood-onset [Crohn's disease]," co-senior authors Matthias Zilbauer, a researcher at the University of Cambridge and Cambridge University Hospitals Trust, and Sarah Teichmann, an investigator with the Wellcome Sanger Institute, University of Cambridge, and European Bioinformatics Institute, and their colleagues wrote in Developmental Cell on Monday.

For their study, they generated single-cell RNA-seq profiles for some 90,000 primary intestinal cells from nine fetal samples, seven pediatric Crohn's cases, and eight unaffected controls using the 10x Genomics Chromium platform and Illumina sequencing. Based on these, along with fetal organoid maturation and single-molecule fluorescence in situ hybridization experiments, Zilbauer, Teichmann, and their colleagues identified intestinal cell populations that distinguish developing gut samples from those found in adults. In children with Crohn's disease, on the other hand, they saw epithelial cell activity by transcription factors that are normally limited to fetal roles.

The study, results of which are available at a website, "underscores the importance of unraveling fetal development in understanding disease," the authors wrote.

While stem cells in the adult gut are typically marked by enhanced expression of the stem cell marker LGR5, for example, the team's single-cell profiles from embryonic and fetal cells spanning the first six to 10 weeks of development suggested that early epithelial precursor cells have characteristic and relatively consistent expression of a gene called BEX5.

From these and other results, the authors suggested that "the cycling epithelium undergoes transcriptional transition from uniform epithelium into LGR5-[positive] stem cells and therefore may act as both a primitive stem cell of the early gut and as a progenitor of LGR5-[positive] stem cells later in development."

With single-cell transcriptomes and other insights from maturing fetal organoid samples, meanwhile, the researchers got a look at the gene expression, regulation, and signaling shifts that accompany the maturation of intestinal epithelial cells from the stem cell stage to differentiated cell stages.

"While analogous processes of early epithelial development were previously reported in chicken and mouse … scRNA-seq data provide insights into the diversity and maturity of epithelial cell types found at fetal stages," the authors explained, though they cautioned that "lineage tracing experiments in organoid cultures are necessary to provide evidence on the source of LGR5-[positive] stem cells in humans."

Finally, when they set single-cell gene expression profiles from Crohn's disease cases and controls against available transcriptome data, the investigators saw signs that pediatric Crohn's disease may involve transcription factors that revert to enhanced activity levels found in fetal intestinal cells.

 

"IBD, and particularly [Crohn's disease], are thought to be caused by a complex interplay between the environment and genetic predisposition leading to an irreversibly altered immune response," the authors explained, noting that the latest results "provide evidence in humans that regenerating [Crohn's disease] epithelium shares transcription factor programs otherwise present only in fetal epithelium."

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