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Cells of the human intestinal tract mapped across space and time

View ORCID ProfileR Elmentaite, N Kumasaka, View ORCID ProfileHW King, View ORCID ProfileK Roberts, M Dabrowska, S Pritchard, L Bolt, SF Vieira, View ORCID ProfileL Mamanova, N Huang, View ORCID ProfileI Goh Kai’En, View ORCID ProfileE Stephenson, J Engelbert, View ORCID ProfileRA Botting, A Fleming, View ORCID ProfileE Dann, View ORCID ProfileSN Lisgo, View ORCID ProfileM Katan, S Leonard, View ORCID ProfileTRW Oliver, CE Hook, K Nayak, F Perrone, LS Campos, View ORCID ProfileC Dominguez-Conde, View ORCID ProfileK Polanski, S Van Dongen, M Patel, MD Morgan, View ORCID ProfileJC Marioni, View ORCID ProfileOA Bayraktar, View ORCID ProfileKB Meyer, View ORCID ProfileM Zilbauer, View ORCID ProfileH Uhlig, View ORCID ProfileMR Clatworthy, View ORCID ProfileKT Mahbubani, View ORCID ProfileK Saeb Parsy, View ORCID ProfileM Haniffa, View ORCID ProfileKR James, View ORCID ProfileSA Teichmann
doi: https://doi.org/10.1101/2021.04.07.438755
R Elmentaite
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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N Kumasaka
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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HW King
2Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
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K Roberts
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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M Dabrowska
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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S Pritchard
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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L Bolt
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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SF Vieira
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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L Mamanova
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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N Huang
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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I Goh Kai’En
3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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E Stephenson
3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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J Engelbert
3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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RA Botting
3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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A Fleming
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
4Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK
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E Dann
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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SN Lisgo
3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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M Katan
7Structural and Molecular Biology, Division of Biosciences, University College London WC1E 6BT, UK
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S Leonard
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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TRW Oliver
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
8Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, United Kingdom of Great Britain and Northern Ireland
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CE Hook
8Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, United Kingdom of Great Britain and Northern Ireland
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K Nayak
10Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
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F Perrone
10Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
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LS Campos
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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C Dominguez-Conde
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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K Polanski
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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S Van Dongen
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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M Patel
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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MD Morgan
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
6Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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JC Marioni
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, CB10 1SD, UK
6Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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OA Bayraktar
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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KB Meyer
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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M Zilbauer
9Wellcome Trust – MRC Cambridge Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge CB2 0SZ, UK
10Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK
11Department of Paediatric Gastroenterology, Hepatology and Nutrition, Cambridge University Hospitals Trust, Cambridge, CB2 0QQ, UK
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H Uhlig
12Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK
13Department of Paediatrics, University of Oxford, Oxford, OX1 2JD, UK
14NIHR Oxford Biomedical Research Centre, Oxford, OX3 7JX, UK
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MR Clatworthy
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
4Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK
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KT Mahbubani
15Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, UK
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K Saeb Parsy
15Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, CB2 0QQ, UK
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M Haniffa
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
3Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
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KR James
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
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  • For correspondence: kj7@sanger.ac.uk st9@sanger.ac.uk
SA Teichmann
1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 ISA, UK
16Theory of Condensed Matter Group, Cavendish Laboratory/Department of Physics, University of Cambridge, Cambridge CB3 0HE, UK
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  • For correspondence: kj7@sanger.ac.uk st9@sanger.ac.uk
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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. To comprehensively map cell lineages in the healthy developing, pediatric and adult human gut from ten distinct anatomical regions, as well as draining lymph nodes, we used singlecell RNA-seq and VDJ analysis of roughly one third of a million cells. This reveals the presence of BEST4+ absorptive cells throughout the human intestinal tract, demonstrating the existence of this cell type beyond the colon for the first time. Furthermore, we implicate IgG sensing as a novel function of intestinal tuft cells, and link these cells to the pathogenesis of inflammatory bowel disease. We define novel glial and neuronal cell populations in the developing enteric nervous system, and predict cell-type specific expression of Hirschsprung’s disease-associated genes. Finally, using a systems approach, we identify key cell players across multiple cell lineages driving secondary lymphoid tissue formation 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. These data provide an unprecedented catalogue of intestinal cells, and new insights into cellular programs in development, homeostasis and disease.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.gutcellatlas.org

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Cells of the human intestinal tract mapped across space and time
R Elmentaite, N Kumasaka, HW King, K Roberts, M Dabrowska, S Pritchard, L Bolt, SF Vieira, L Mamanova, N Huang, I Goh Kai’En, E Stephenson, J Engelbert, RA Botting, A Fleming, E Dann, SN Lisgo, M Katan, S Leonard, TRW Oliver, CE Hook, K Nayak, F Perrone, LS Campos, C Dominguez-Conde, K Polanski, S Van Dongen, M Patel, MD Morgan, JC Marioni, OA Bayraktar, KB Meyer, M Zilbauer, H Uhlig, MR Clatworthy, KT Mahbubani, K Saeb Parsy, M Haniffa, KR James, SA Teichmann
bioRxiv 2021.04.07.438755; doi: https://doi.org/10.1101/2021.04.07.438755
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Cells of the human intestinal tract mapped across space and time
R Elmentaite, N Kumasaka, HW King, K Roberts, M Dabrowska, S Pritchard, L Bolt, SF Vieira, L Mamanova, N Huang, I Goh Kai’En, E Stephenson, J Engelbert, RA Botting, A Fleming, E Dann, SN Lisgo, M Katan, S Leonard, TRW Oliver, CE Hook, K Nayak, F Perrone, LS Campos, C Dominguez-Conde, K Polanski, S Van Dongen, M Patel, MD Morgan, JC Marioni, OA Bayraktar, KB Meyer, M Zilbauer, H Uhlig, MR Clatworthy, KT Mahbubani, K Saeb Parsy, M Haniffa, KR James, SA Teichmann
bioRxiv 2021.04.07.438755; doi: https://doi.org/10.1101/2021.04.07.438755

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