Abstract
SummaryHuman 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.
Highlights
Development of the human intestine is a highly complex process that requires synergy between a wide range of cell types
Single-Cell Map of the Human Embryonic, Fetal and Pediatric Gut Human embryos with a post-conceptional age ranging from 6 to 10 weeks were dissected to remove the intestinal tube, which was divided into proximal small stem cells (Fordham et al, 2013)
We show that PTCH1 expression forms ripples with high expression by cells located around the epithelium and SMCs that were marked by PLA2G2A expression in scRNA-seq data (Figures 4C and S3A) as well as in situ (Figure S3C, white arrows)
Summary
Development of the human intestine is a highly complex process that requires synergy between a wide range of cell types. Environmentally triggered alterations in early development have been implicated in a range of immune-mediated pathologies, including inflammatory bowel diseases (IBD) (Sonntag et al, 2007; Cilieborg et al, 2012; DupaulChicoine et al, 2013; Kraiczy et al, 2016). The human intestinal tract develops from the endodermal germ cell layer of the embryo, beginning with the formation of a simple tube at 3–4 weeks post-conception (PCW). While little is known about the villus formation in humans, two mechanisms have been proposed in model organisms: mesenchymal clustering in mice and the force generated by smooth muscle in chickens (Karlsson et al, 2000; Walton et al, 2012, 2016a, 2016b; Shyer et al, 2013). While there are significant differences between the two models, both employ similar signaling, including gradients of hedgehog (HH), PDGF, and bone morphogenetic protein (BMP) ligands (Kolterud et al, 2009; Korinek et al, 1998; Kurahashi et al, 2008; Madison et al, 2005; Geske et al, 2008; Shyer et al, 2015)
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