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A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

View ORCID ProfilePeng He, View ORCID ProfileKyungtae Lim, View ORCID ProfileDawei Sun, View ORCID ProfileJan Patrick Pett, Quitz Jeng, Krzysztof Polanski, Ziqi Dong, View ORCID ProfileLiam Bolt, Laura Richardson, View ORCID ProfileLira Mamanova, Monika Dabrowska, Anna Wilbrey-Clark, View ORCID ProfileElo Madissoon, View ORCID ProfileZewen Kelvin Tuong, View ORCID ProfileEmma Dann, View ORCID ProfileChenqu Suo, View ORCID ProfileIsaac Goh Kai’En, Xiaoling He, View ORCID ProfileRoger Barker, View ORCID ProfileSarah A Teichmann, View ORCID ProfileJohn C. Marioni, View ORCID ProfileKerstin B Meyer, View ORCID ProfileEmma L Rawlins
doi: https://doi.org/10.1101/2022.01.11.474933
Peng He
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK.
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Kyungtae Lim
4Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
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Dawei Sun
4Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
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Jan Patrick Pett
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Quitz Jeng
4Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
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Krzysztof Polanski
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Ziqi Dong
4Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
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Liam Bolt
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Laura Richardson
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Lira Mamanova
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Monika Dabrowska
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Anna Wilbrey-Clark
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Elo Madissoon
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK.
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Zewen Kelvin Tuong
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
5Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK
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Emma Dann
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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Chenqu Suo
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
10Department of Paediatrics, Cambridge University Hospitals, Hills Road, Cambridge CB2 0 QQ, UK
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Isaac Goh Kai’En
6Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
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Xiaoling He
7John van Geest Centre for Brain Repair, Department of Clinical Neurosciences and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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Roger Barker
7John van Geest Centre for Brain Repair, Department of Clinical Neurosciences and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
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Sarah A Teichmann
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
8Dept Physics/Cavendish Laboratory, University of Cambridge, JJ Thomson Ave, Cambridge CB3 0HE, UK
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John C. Marioni
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
3European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK.
9Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
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Kerstin B Meyer
2Wellcome Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
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  • For correspondence: km16@sanger.ac.uk e.rawlins@gurdon.cam.ac.uk
Emma L Rawlins
4Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QN, UK.
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  • For correspondence: km16@sanger.ac.uk e.rawlins@gurdon.cam.ac.uk
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Abstract

We present a multiomic cell atlas of human lung development that combines single cell RNA and ATAC sequencing, high throughput spatial transcriptomics and single cell imaging. Coupling single cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial and erythrocyte/leukocyte compartments from 5-22 post conception weeks. We identify new cell states in all compartments. These include developmental-specific secretory progenitors that resemble cells in adult fibrotic lungs and a new subtype of neuroendocrine cell related to human small cell lung cancer; observations which strengthen the connections between development and disease/regeneration. Our datasets are available for the community to download and interact with through our web interface (https://fetal-lung.cellgeni.sanger.ac.uk). Finally, to illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signalling and transcription factor hierarchies which we test using organoid models.

Highlights

  • Spatiotemporal atlas of human lung development from 5-22 post conception weeks identifies 147 cell types/states.

  • Tracking the developmental origins of multiple cell compartments, including new progenitor states.

  • Functional diversity of fibroblasts in distinct anatomical signalling niches.

  • Resource applied to interrogate and experimentally test the transcription factor code controlling neuroendocrine cell heterogeneity and the origins of small cell lung cancer.

Competing Interest Statement

In the past 3 years, S.A.T. has worked as a consultant for Genentech, Roche and Transition Bio, is a remunerated member of the scientific advisory boards of Biogen, GlaxoSmithKline, Foresite Labs and Qiagen and is an equity holder of Transition Bio.

Footnotes

  • ↵1 Joint first authors

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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Posted January 11, 2022.
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A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates
Peng He, Kyungtae Lim, Dawei Sun, Jan Patrick Pett, Quitz Jeng, Krzysztof Polanski, Ziqi Dong, Liam Bolt, Laura Richardson, Lira Mamanova, Monika Dabrowska, Anna Wilbrey-Clark, Elo Madissoon, Zewen Kelvin Tuong, Emma Dann, Chenqu Suo, Isaac Goh Kai’En, Xiaoling He, Roger Barker, Sarah A Teichmann, John C. Marioni, Kerstin B Meyer, Emma L Rawlins
bioRxiv 2022.01.11.474933; doi: https://doi.org/10.1101/2022.01.11.474933
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A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates
Peng He, Kyungtae Lim, Dawei Sun, Jan Patrick Pett, Quitz Jeng, Krzysztof Polanski, Ziqi Dong, Liam Bolt, Laura Richardson, Lira Mamanova, Monika Dabrowska, Anna Wilbrey-Clark, Elo Madissoon, Zewen Kelvin Tuong, Emma Dann, Chenqu Suo, Isaac Goh Kai’En, Xiaoling He, Roger Barker, Sarah A Teichmann, John C. Marioni, Kerstin B Meyer, Emma L Rawlins
bioRxiv 2022.01.11.474933; doi: https://doi.org/10.1101/2022.01.11.474933

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