Cells of the human intestinal tract mapped across space and time

Rasa Elmentaite; Natsuhiko Kumasaka; Kenny Roberts; Aaron Fleming; Emma Dann; Hamish W King; Vitalii Kleshchevnikov; Monika Dabrowska; Sophie Pritchard; Liam Bolt; Sara F Vieira; Lira Mamanova; Ni Huang; Francesca Perrone; Issac Goh Kai'En; Steven N Lisgo; Matilda Katan; Steven Leonard; Thomas R W Oliver; C Elizabeth Hook; Komal Nayak; Lia S Campos; Cecilia Domínguez Conde; Emily Stephenson; Justin Engelbert; Rachel A Botting; Krzysztof Polanski; Stijn van Dongen; Minal Patel; Michael D Morgan; John C Marioni; Omer Ali Bayraktar; Kerstin B Meyer; Xiaoling He; Roger A Barker; Holm H Uhlig; Krishnaa T Mahbubani; Kourosh Saeb-Parsy; Matthias Zilbauer; Menna R Clatworthy; Muzlifah Haniffa; Kylie R James; Sarah A Teichmann

doi:10.1038/s41586-021-03852-1

Cells of the human intestinal tract mapped across space and time

Rasa Elmentaite, Natsuhiko Kumasaka, Kenny Roberts, Aaron Fleming, Emma Dann, Hamish W King, Vitalii Kleshchevnikov, Monika Dabrowska, Sophie Pritchard, Liam Bolt, Sara F Vieira, Lira Mamanova, Ni Huang, Francesca Perrone, Issac Goh Kai'En, Steven N Lisgo, Matilda Katan, Steven Leonard, Thomas R W Oliver, C Elizabeth HookKomal Nayak, Lia S Campos, Cecilia Domínguez Conde, Emily Stephenson, Justin Engelbert, Rachel A Botting, Krzysztof Polanski, Stijn van Dongen, Minal Patel, Michael D Morgan, John C Marioni, Omer Ali Bayraktar, Kerstin B Meyer, Xiaoling He, Roger A Barker, Holm H Uhlig, Krishnaa T Mahbubani, Kourosh Saeb-Parsy, Matthias Zilbauer, Menna R Clatworthy, Muzlifah Haniffa, Kylie R James, Sarah A Teichmann

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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. 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.

Original language	English
Pages (from-to)	250-255
Number of pages	6
Journal	Nature
Volume	597
Issue number	7875
DOIs	https://doi.org/10.1038/s41586-021-03852-1
Publication status	Published - 8 Sept 2021

Bibliographical note

Acknowledgements
We acknowledge support from the Wellcome Sanger Cytometry Core Facility, Cellular Genetics Informatics team, Cellular Generation and Phenotyping (CGaP) and Core DNA Pipelines. This work was financially supported by the Wellcome Trust (W1T20694, S.A.T.; 203151/Z/16/Z, R. A. Barker.); the European Research Council (646794, ThDefine, S.A.T.); an MRC New Investigator Research Grant (MR/T001917/1, M.Z.); and a project grant from the Great Ormond Street Hospital Children’s Charity, Sparks (V4519, M.Z.). The human embryonic and fetal material was provided by the Joint MRC/Wellcome (MR/R006237/1) Human Developmental Biology Resource (https://www.hdbr.org/). K.R.J. holds a Non-Stipendiary Junior Research Fellowship from Christ’s College, University of Cambridge. M.R.C. is supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1) and a Wellcome Trust Investigator Award (220268/Z/20/Z). H.W.K. is funded by a Sir Henry Wellcome Fellowship (213555/Z/18/Z). A.F. is funded by a Wellcome PhD Studentship (102163/B/13/Z). K.T.M. is funded by an award from the Chan Zuckerberg Initiative. H.H.U. is supported by the Oxford Biomedical Research Centre (BRC) and the The Leona M. and Harry B. Helmsley Charitable Trust. We thank A. Chakravarti and S. Chatterjee for their contribution to the analysis of the enteric nervous system. We also thank R. Lindeboom and C. Talavera-Lopez for support with epithelium and Visium analysis, respectively; C. Tudor, T. Li and O. Tarkowska for image processing and infrastructure support; A. Wilbrey-Clark and T. Porter for support with Visium library preparation; A. Ross and J. Park for access to and handling of fetal tissue; A. Hunter for assistance in protocol development; D. Fitzpatrick for discussion on developmental intestinal disorders; and J. Eliasova for the graphical images. We thank the tissue donors and their families, and the Cambridge Biorepository for Translational Medicine and Human Developmental Biology Resource, for access to human tissue. This publication is part of the Human Cell Atlas: https://www.humancellatlas.org/publications.

Data Availability Statement

The expression data for fetal and adult regions is available on an interactive website: https://www.gutcellatlas.org/. Raw sequencing data are available at ArrayExpress (https://www.ebi.ac.uk/arrayexpress) with accession numbers E-MTAB-9543, E-MTAB-9536, E-MTAB-9532, E-MTAB-9533 and E-MTAB-10386. Previously published first trimester and paediatric data are available at ArrayExpress (E-MTAB-8901)1. For the purpose of Open Access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Source data are provided with this paper.

Code availability
Processed single-cell RNA sequencing objects are available for online visualization and download at https://www.gutcellatlas.org/. The code generated during this study is available at Github: https://github.com/Teichlab/SpaceTimeGut, https://github.com/vitkl/fetal_gut_mapping/, https://github.com/natsuhiko/PHM

Keywords

Adult
Aging
Animals
Child
Crohn Disease/pathology
Datasets as Topic
Enteric Nervous System/anatomy & histology
Epithelial Cells/cytology
Female
Fetus/anatomy & histology
Health
Humans
Intestines/cytology
Lymph Nodes/cytology
Mice
Mice, Inbred C57BL
Organogenesis
Receptors, IgG/metabolism
Signal Transduction
Spatio-Temporal Analysis
Time Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cite this

Elmentaite, R., Kumasaka, N., Roberts, K., Fleming, A., Dann, E., King, H. W., Kleshchevnikov, V., Dabrowska, M., Pritchard, S., Bolt, L., Vieira, S. F., Mamanova, L., Huang, N., Perrone, F., Goh Kai'En, I., Lisgo, S. N., Katan, M., Leonard, S., Oliver, T. R. W., ... Teichmann, S. A. (2021). Cells of the human intestinal tract mapped across space and time. Nature, 597(7875), 250-255. https://doi.org/10.1038/s41586-021-03852-1

Elmentaite, R, Kumasaka, N, Roberts, K, Fleming, A, Dann, E, King, HW, Kleshchevnikov, V, Dabrowska, M, Pritchard, S, Bolt, L, Vieira, SF, Mamanova, L, Huang, N, Perrone, F, Goh Kai'En, I, Lisgo, SN, Katan, M, Leonard, S, Oliver, TRW, Hook, CE, Nayak, K, Campos, LS, Domínguez Conde, C, Stephenson, E, Engelbert, J, Botting, RA, Polanski, K, van Dongen, S, Patel, M, Morgan, MD, Marioni, JC, Bayraktar, OA, Meyer, KB, He, X, Barker, RA, Uhlig, HH, Mahbubani, KT, Saeb-Parsy, K, Zilbauer, M, Clatworthy, MR, Haniffa, M, James, KR & Teichmann, SA 2021, 'Cells of the human intestinal tract mapped across space and time', Nature, vol. 597, no. 7875, pp. 250-255. https://doi.org/10.1038/s41586-021-03852-1

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title = "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.",

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author = "Rasa Elmentaite and Natsuhiko Kumasaka and Kenny Roberts and Aaron Fleming and Emma Dann and King, {Hamish W} and Vitalii Kleshchevnikov and Monika Dabrowska and Sophie Pritchard and Liam Bolt and Vieira, {Sara F} and Lira Mamanova and Ni Huang and Francesca Perrone and {Goh Kai'En}, Issac and Lisgo, {Steven N} and Matilda Katan and Steven Leonard and Oliver, {Thomas R W} and Hook, {C Elizabeth} and Komal Nayak and Campos, {Lia S} and {Dom{\'i}nguez Conde}, Cecilia and Emily Stephenson and Justin Engelbert and Botting, {Rachel A} and Krzysztof Polanski and {van Dongen}, Stijn and Minal Patel and Morgan, {Michael D} and Marioni, {John C} and Bayraktar, {Omer Ali} and Meyer, {Kerstin B} and Xiaoling He and Barker, {Roger A} and Uhlig, {Holm H} and Mahbubani, {Krishnaa T} and Kourosh Saeb-Parsy and Matthias Zilbauer and Clatworthy, {Menna R} and Muzlifah Haniffa and James, {Kylie R} and Teichmann, {Sarah A}",

note = "Acknowledgements We acknowledge support from the Wellcome Sanger Cytometry Core Facility, Cellular Genetics Informatics team, Cellular Generation and Phenotyping (CGaP) and Core DNA Pipelines. This work was financially supported by the Wellcome Trust (W1T20694, S.A.T.; 203151/Z/16/Z, R. A. Barker.); the European Research Council (646794, ThDefine, S.A.T.); an MRC New Investigator Research Grant (MR/T001917/1, M.Z.); and a project grant from the Great Ormond Street Hospital Children{\textquoteright}s Charity, Sparks (V4519, M.Z.). The human embryonic and fetal material was provided by the Joint MRC/Wellcome (MR/R006237/1) Human Developmental Biology Resource (https://www.hdbr.org/). K.R.J. holds a Non-Stipendiary Junior Research Fellowship from Christ{\textquoteright}s College, University of Cambridge. M.R.C. is supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1) and a Wellcome Trust Investigator Award (220268/Z/20/Z). H.W.K. is funded by a Sir Henry Wellcome Fellowship (213555/Z/18/Z). A.F. is funded by a Wellcome PhD Studentship (102163/B/13/Z). K.T.M. is funded by an award from the Chan Zuckerberg Initiative. H.H.U. is supported by the Oxford Biomedical Research Centre (BRC) and the The Leona M. and Harry B. Helmsley Charitable Trust. We thank A. Chakravarti and S. Chatterjee for their contribution to the analysis of the enteric nervous system. We also thank R. Lindeboom and C. Talavera-Lopez for support with epithelium and Visium analysis, respectively; C. Tudor, T. Li and O. Tarkowska for image processing and infrastructure support; A. Wilbrey-Clark and T. Porter for support with Visium library preparation; A. Ross and J. Park for access to and handling of fetal tissue; A. Hunter for assistance in protocol development; D. Fitzpatrick for discussion on developmental intestinal disorders; and J. Eliasova for the graphical images. We thank the tissue donors and their families, and the Cambridge Biorepository for Translational Medicine and Human Developmental Biology Resource, for access to human tissue. This publication is part of the Human Cell Atlas: https://www.humancellatlas.org/publications.",

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doi = "10.1038/s41586-021-03852-1",

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journal = "Nature",

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TY - JOUR

T1 - Cells of the human intestinal tract mapped across space and time

AU - Elmentaite, Rasa

AU - Kumasaka, Natsuhiko

AU - Roberts, Kenny

AU - Fleming, Aaron

AU - Dann, Emma

AU - King, Hamish W

AU - Kleshchevnikov, Vitalii

AU - Dabrowska, Monika

AU - Pritchard, Sophie

AU - Bolt, Liam

AU - Vieira, Sara F

AU - Mamanova, Lira

AU - Huang, Ni

AU - Perrone, Francesca

AU - Goh Kai'En, Issac

AU - Lisgo, Steven N

AU - Katan, Matilda

AU - Leonard, Steven

AU - Oliver, Thomas R W

AU - Hook, C Elizabeth

AU - Nayak, Komal

AU - Campos, Lia S

AU - Domínguez Conde, Cecilia

AU - Stephenson, Emily

AU - Engelbert, Justin

AU - Botting, Rachel A

AU - Polanski, Krzysztof

AU - van Dongen, Stijn

AU - Patel, Minal

AU - Morgan, Michael D

AU - Marioni, John C

AU - Bayraktar, Omer Ali

AU - Meyer, Kerstin B

AU - He, Xiaoling

AU - Barker, Roger A

AU - Uhlig, Holm H

AU - Mahbubani, Krishnaa T

AU - Saeb-Parsy, Kourosh

AU - Zilbauer, Matthias

AU - Clatworthy, Menna R

AU - Haniffa, Muzlifah

AU - James, Kylie R

AU - Teichmann, Sarah A

N1 - Acknowledgements We acknowledge support from the Wellcome Sanger Cytometry Core Facility, Cellular Genetics Informatics team, Cellular Generation and Phenotyping (CGaP) and Core DNA Pipelines. This work was financially supported by the Wellcome Trust (W1T20694, S.A.T.; 203151/Z/16/Z, R. A. Barker.); the European Research Council (646794, ThDefine, S.A.T.); an MRC New Investigator Research Grant (MR/T001917/1, M.Z.); and a project grant from the Great Ormond Street Hospital Children’s Charity, Sparks (V4519, M.Z.). The human embryonic and fetal material was provided by the Joint MRC/Wellcome (MR/R006237/1) Human Developmental Biology Resource (https://www.hdbr.org/). K.R.J. holds a Non-Stipendiary Junior Research Fellowship from Christ’s College, University of Cambridge. M.R.C. is supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1) and a Wellcome Trust Investigator Award (220268/Z/20/Z). H.W.K. is funded by a Sir Henry Wellcome Fellowship (213555/Z/18/Z). A.F. is funded by a Wellcome PhD Studentship (102163/B/13/Z). K.T.M. is funded by an award from the Chan Zuckerberg Initiative. H.H.U. is supported by the Oxford Biomedical Research Centre (BRC) and the The Leona M. and Harry B. Helmsley Charitable Trust. We thank A. Chakravarti and S. Chatterjee for their contribution to the analysis of the enteric nervous system. We also thank R. Lindeboom and C. Talavera-Lopez for support with epithelium and Visium analysis, respectively; C. Tudor, T. Li and O. Tarkowska for image processing and infrastructure support; A. Wilbrey-Clark and T. Porter for support with Visium library preparation; A. Ross and J. Park for access to and handling of fetal tissue; A. Hunter for assistance in protocol development; D. Fitzpatrick for discussion on developmental intestinal disorders; and J. Eliasova for the graphical images. We thank the tissue donors and their families, and the Cambridge Biorepository for Translational Medicine and Human Developmental Biology Resource, for access to human tissue. This publication is part of the Human Cell Atlas: https://www.humancellatlas.org/publications.

PY - 2021/9/8

Y1 - 2021/9/8

N2 - 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.

AB - 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.

KW - Adult

KW - Aging

KW - Animals

KW - Child

KW - Crohn Disease/pathology

KW - Datasets as Topic

KW - Enteric Nervous System/anatomy & histology

KW - Epithelial Cells/cytology

KW - Female

KW - Fetus/anatomy & histology

KW - Health

KW - Humans

KW - Intestines/cytology

KW - Lymph Nodes/cytology

KW - Mice

KW - Mice, Inbred C57BL

KW - Organogenesis

KW - Receptors, IgG/metabolism

KW - Signal Transduction

KW - Spatio-Temporal Analysis

KW - Time Factors

U2 - 10.1038/s41586-021-03852-1

DO - 10.1038/s41586-021-03852-1

M3 - Article

C2 - 34497389

SN - 0028-0836

VL - 597

SP - 250

EP - 255

JO - Nature

JF - Nature

IS - 7875

ER -

Cells of the human intestinal tract mapped across space and time

Abstract

Bibliographical note

Data Availability Statement

Keywords

UN SDGs

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