Abstract

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

Highlights

  • Intestinal tract physiology relies on the integrated contribution of multiple cell lineages, the relative abundance and cell networking of which fluctuate from embryonic development to adulthood

  • We investigated the differentiation of neural cells from enteric neural crest cell (ENCC) progenitors (Fig. 3a, b) that were present in the dataset from 6.5 PCW (Extended Data Fig. 8a)

  • Innate lymphoid cell progenitors (ILCPs) were transcriptionally comparable to fetal liver ILCPs30 (Extended Data Fig. 10e), and were found both in fetal mesenteric lymph nodes (mLN) and in embryonic gut, whereas NCR+ and NCR− type 3 innate lymphoid cells (ILC3s) were expanded across gut regions throughout 6–17 PCW (Extended Data Fig. 10f). This suggests that lymphoid tissue inducers (LTi)-like ILC3 subsets are expanded during the development of gut-associated lymphoid tissues, but not during the development of mLN

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Summary

6–11 PCW 12–17 PCW

Glia Glia 1 Differentiating glia Glia 2 Glia 3 Neuroblast Cycling neuroblast Branch A1 Branch A2 Branch A3 Branch A4 Branch B1 Branch B2 Branch B3. Innate lymphoid cell progenitors (ILCPs) were transcriptionally comparable to fetal liver ILCPs30 (Extended Data Fig. 10e), and were found both in fetal mLN and in embryonic gut, whereas NCR+ and NCR− type 3 innate lymphoid cells (ILC3s) were expanded across gut regions throughout 6–17 PCW (Extended Data Fig. 10f) This suggests that LTi-like ILC3 subsets are expanded during the development of gut-associated lymphoid tissues, but not during the development of mLN. To visualize the recruitment of naive immune cell subsets to activated mLTo, we used cell2location[34] to perform spatial mapping of single-cell transcriptomes to 10x Genomics Visium spatial zones in 17 PCW fetal ileums (Fig. 4e, Methods) In this analysis, we captured tissue zones with expression of mLTo marker genes (CCL19, CCL21 and CXCL13) (Extended Data Fig. 15a–c) that were likely to correspond to developing secondary lymphoid organs. Adult ILC3s and fetal ILCPs and NCR+ ILC3s were among the top cells that were enriched for the expression of genes associated with Crohn’s disease (Fig. 4f, Extended Data Fig. 15f)

Discussion
KCNN3 C7
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