Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease
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ABSTRACT:
PROVIDER: PRJEB37689 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we performed single-cell transcriptional profiling of human embryonic and fetal gut samples obtained from 9 human embryos spanning ages 6-10 PCW and three regions (duo-jejunum, ileum and colon). Additionally, we profile mucosal biopsies from the terminal ileum of healthy children aged 4-12 years (n = 8) as well as a group of children newly diagnosed with Crohn’s disease (CD) (n = 7), a common form of IBD. Tissue samples were treated using an enzymatic dissociation protocol and single cell suspensions were then processed using the 3’v2 10x Genomics Chromium workflow. In a subset of samples, the intestinal epithelial cell fraction was enriched by performing magnetic bead sorting for EPCAM. In total, we generate single cell transcriptomes of ~90,000 primary human intestinal cells providing a rich resource and detailed roadmap. Using this data as well as scRNAseq profiles of human fetal gut derived organoids we describe embryonic and fetal epithelium composition, trace their differentiation dynamics and signaling partners, and provide links to regenerating Crohn’s disease epithelium.
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Project description:Human gut development requires the orchestrated interaction of differentiating cell types. Here, we generate an in-depth single-cell map of the developing human intestine at 6-10 weeks post-conception. Our analysis reveals the transcriptional profile of cycling epithelial precursor cells; distinct from LGR5-expressing cells. We propose that these cells may contribute to differentiated cell subsets via the generation of LGR5-expressing stem cells and receive signals from surrounding mesenchymal cells. Furthermore, we draw parallels between the transcriptomes of ex vivo tissues and in vitro fetal organoids, revealing the maturation of organoid cultures in a dish. Lastly, we compare scRNA-seq profiles from pediatric Crohn's disease epithelium alongside matched healthy controls to reveal disease-associated changes in the epithelial composition. Contrasting these with the fetal profiles reveals the re-activation of fetal transcription factors in Crohn's disease. Our study provides a resource available at www.gutcellatlas.org, and underscores the importance of unraveling fetal development in understanding disease.
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Project description:Crohn’s disease (CD) is a subtype of inflammatory bowel disease (IBD) characterized by transmural disease. The concept of transmural healing (TH) has been proposed as an indicator of deep clinical remission of CD and as a predictor of favorable treatment endpoints. Understanding the pathophysiology involved in transmural disease is critical to achieving these endpoints. How-ever, most studies have focused on the colon intestinal mucosa, overlooking the contribution of the colon intestinal wall in Crohn’s disease. Multi-omics approaches have provided new avenues for exploring the pathogenesis of Crohn’s disease and identifying potential biomarkers. Therefore, we analyzed and compared the gene and protein expression and dysregulated biological functions in the distinct tissue compartments of mucosa and submucosa/wall of colon resections from CD patients. We aimed to use transcriptomic and proteomic technologies to compare immune and mesenchymal cell profiles and pathways in the mucosal and submucosa/wall compartments to better understand refractory disease elements to achieve transmural healing. We employed a comprehensive multi-omics approach to investi-gate the molecular profiles of the colon mucosa and submucosa/wall compartments in patients with chronic Crohn’s disease. The results revealed similarities and differences in gene and protein ex-pression profiles, metabolic mechanisms, and immune and non-immune pathways between these two compartments. Additionally, the identification of protein isoforms highlights the complex molecular mechanisms underlying this disease. These findings have the potential to inform the development of novel therapeutic strategies to achieve TH.
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