Cells of the human intestinal tract mapped across space and time

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.

References 85

1. 1.
   Single-Cell Sequencing of Developing Human Gut Reveals Transcriptional Links to Childhood Crohn’s Disease · 2020

   No notice
2. 2.

   Holloway EM, et al. Mapping development of the human intestinal niche at single-cell resolution. Cell Stem Cell. 2021;28:568-580.e4.

   Not in our library10.1016/j.stem.2020.11.008

3. 3.
   Spatiotemporal analysis of human intestinal development at single-cell resolution · 2021

   No notice
4. 4.

   James KR, et al. Distinct microbial and immune niches of the human colon. Nat. Immunol. 2020;21:343-353.

   Not in our library10.1038/s41590-020-0602-z

5. 5.
   Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease · 2018

   No notice
6. 6.

   Smillie CS, et al. Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell. 2019;178:714-730.e22.

   Not in our library10.1016/j.cell.2019.06.029

7. 7.

   Boland BS, et al. Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses. Sci. Immunol. 2020;5:eabb4432.

   Not in our library10.1126/sciimmunol.abb4432

8. 8.

   Corridoni D, et al. Single-cell atlas of colonic CD8+ T cells in ulcerative colitis. Nat. Med. 2020;26:1-11.

   Not in our library10.1038/s41591-020-1003-4

9. 9.

   Huang B, et al. Mucosal profiling of pediatric-onset colitis and ibd reveals common pathogenics and therapeutic pathways. Cell. 2019;179:1160-1176.e24.

   Not in our library10.1016/j.cell.2019.10.027

10. 10.

    Martin JC, et al. Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell. 2019;178:1493-1508.e20.

    Not in our library10.1016/j.cell.2019.08.008

11. 11.

    Haniffa, M. et al. (2021) A roadmap for the Human Developmental Cell Atlas. Nature, 10.1038/s41586-021-03620-1 (2021).

    Not in our library10.1038/s41586-021-03620-1

12. 12.

    Ito G, et al. Lineage-specific expression of bestrophin-2 and bestrophin-4 in human intestinal epithelial cells. PLoS ONE. 2013;8:e79693.

    Not in our library10.1371/journal.pone.0079693

13. 13.

    Parikh K, et al. Colonic epithelial cell diversity in health and inflammatory bowel disease. Nature. 2019;567:49-55.

    Not in our library10.1038/s41586-019-0992-y

14. 14.

    Dann, E., Henderson, N. C., Teichmann, S. A., Morgan, M. D. & Marioni, J. C. Milo: differential abundance testing on single-cell data using k-NN graphs. Preprint at 10.1101/2020.11.23.393769 (2020).

    Not in our library10.1038/s41587-021-01033-z

15. 15.
    SARS-CoV-2 productively infects human gut enterocytes · 2020

    No notice
16. 16.

    Beumer J, et al. High-resolution mRNA and secretome atlas of human enteroendocrine cells. Cell. 2020;181:1291-1306.e19.

    Not in our library10.1016/j.cell.2020.04.036

17. 17.

    Levine AS, Winsky-Sommerer R, Huitron-Resendiz S, Grace MK, de Lecea L. Injection of neuropeptide W into paraventricular nucleus of hypothalamus increases food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005;288:R1727-R1732.

    Not in our library10.1152/ajpregu.00638.2003

18. 18.

    Roberts GP, et al. Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling. Diabetes. 2019;68:1062-1072.

    Not in our library10.2337/db18-0883

19. 19.

    Gehart H, et al. Identification of enteroendocrine regulators by real-time single-cell differentiation mapping. Cell. 2019;176:1158-1173.e16.

    Not in our library10.1016/j.cell.2018.12.029

20. 20.

    Beumer J, Gehart H, Clevers H. Enteroendocrine dynamics – new tools reveal hormonal plasticity in the gut. Endocr. Rev. 2020;41:695-706.

    Not in our library10.1210/endrev/bnaa018

21. 21.

    Moreno-Fierros L, Verdín-Terán SL, García-Hernández AL. Intraperitoneal immunization with Cry1Ac protoxin from Bacillus thuringiensis provokes upregulation of Fc-gamma-II/and Fc-gamma-III receptors associated with IgG in the intestinal epithelium of mice. Scand. J. Immunol. 2015;82:35-47.

    Not in our library10.1111/sji.12305

22. 22.

    Morarach K, et al. Diversification of molecularly defined myenteric neuron classes revealed by single-cell RNA sequencing. Nat. Neurosci. 2021;24:34-46.

    Not in our library10.1038/s41593-020-00736-x

23. 23.

    May-Zhang AA, et al. Combinatorial transcriptional profiling of mouse and human enteric neurons identifies shared and disparate subtypes in situ. Gastroenterology. 2021;160:755-770.e26.

    Not in our library10.1053/j.gastro.2020.09.032

24. 24.

    Memic F, et al. Transcription and signaling regulators in developing neuronal subtypes of mouse and human enteric nervous system. Gastroenterology. 2018;154:624-636.

    Not in our library10.1053/j.gastro.2017.10.005

25. 25.

    Tang CS-M, et al. Identification of genes associated with Hirschsprung disease, based on whole-genome sequence analysis, and potential effects on enteric nervous system development. Gastroenterology. 2018;155:1908-1922.e5.

    Not in our library10.1053/j.gastro.2018.09.012

26. 26.

    Zhang Z, et al. Sporadic Hirschsprung disease: mutational spectrum and novel candidate genes revealed by next-generation sequencing. Sci. Rep. 2017;7:14796.

    Not in our library10.1038/s41598-017-14835-6

27. 27.

    Bondurand N, Southard-Smith EM. Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: old and new players. Dev. Biol. 2016;417:139-157.

    Not in our library10.1016/j.ydbio.2016.06.042

28. 28.

    Hoorweg K, Cupedo T. Development of human lymph nodes and Peyer’s patches. Semin. Immunol. 2008;20:164-170.

    Not in our library10.1016/j.smim.2008.02.003

29. 29.

    Krishnamurty AT, Turley SJ. Lymph node stromal cells: cartographers of the immune system. Nat. Immunol. 2020;21:369-380.

    Not in our library10.1038/s41590-020-0635-3

30. 30.

    Popescu D-M, et al. Decoding human fetal liver haematopoiesis. Nature. 2019;574:365-371.

    Not in our library10.1038/s41586-019-1652-y

31. 31.

    Takeda A, et al. Single-cell survey of human lymphatics unveils marked endothelial cell heterogeneity and mechanisms of homing for neutrophils. Immunity. 2019;51:561-572.e5.

    Not in our library10.1016/j.immuni.2019.06.027

32. 32.

    Rodda LB, et al. Single-cell RNA sequencing of lymph node stromal cells reveals niche-associated heterogeneity. Immunity. 2018;48:1014-1028.e6.

    Not in our library10.1016/j.immuni.2018.04.006

33. 33.

    Koning JJ, et al. Nestin-expressing precursors give rise to both endothelial as well as nonendothelial lymph node stromal cells. J. Immunol. 2016;197:2686-2694.

    Not in our library10.4049/jimmunol.1501162

34. 34.

    Kleshchevnikov, V. et al. Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics. Preprint at 10.1101/2020.11.15.378125 (2020).

    Not in our library

35. 35.

    Sura R, Colombel J-F, Van Kruiningen HJ. Lymphatics, tertiary lymphoid organs and the granulomas of Crohn’s disease: an immunohistochemical study. Aliment. Pharmacol. Ther. 2011;33:930-939.

    Not in our library10.1111/j.1365-2036.2011.04605.x

36. 36.

    de Lange KM, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat. Genet. 2017;49:256-261.

    Not in our library10.1038/ng.3760

37. 37.

    Uhlig HH. Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut. 2013;62:1795-1805.

    Not in our library10.1136/gutjnl-2012-303956

38. 38.

    Martín-Nalda A, et al. Severe autoinflammatory manifestations and antibody deficiency due to novel hypermorphic PLCG2 mutations. J. Clin. Immunol. 2020;40:987-1000.

    Not in our library10.1007/s10875-020-00794-7

39. 39.

    Haley PJ. The lymphoid system: a review of species differences. J. Toxicol. Pathol. 2017;30:111-123.

    Not in our library10.1293/tox.2016-0075

40. 40.

    Li N, et al. Memory CD4+ T cells are generated in the human fetal intestine. Nat. Immunol. 2019;20:301-312.

    Not in our library10.1038/s41590-018-0294-9

Cited by papers we hold 11

• BANKSY unifies cell typing and tissue domain segmentation for scalable spatial omics data analysis · 2024
  No notice
• Characteristics of blood–brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells · 2024
  No notice
• Spatially resolved multiomics of human cardiac niches · 2023
  Corrected
• SEACells infers transcriptional and epigenomic cellular states from single-cell genomics data · 2023
  No notice
• Organization of the human intestine at single-cell resolution · 2023
  No notice
• Advances in mixed cell deconvolution enable quantification of cell types in spatial transcriptomic data · 2022
  No notice
• Cross-tissue immune cell analysis reveals tissue-specific features in humans · 2022
  No notice
• Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota · 2022
  No notice
• A spatially resolved atlas of the human lung characterizes a gland-associated immune niche · 2022
  No notice
• Mapping the developing human immune system across organs · 2022
  No notice
• Phenotypic plasticity and genetic control in colorectal cancer evolution · 2022
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.