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

Peng He¹, Kyungtae Lim², Dawei Sun², Jan Patrick Pett³, Quitz Jeng², Krzysztof Polanski³, Ziqi Dong², Liam Bolt³, Laura Richardson³, Lira Mamanova³, Monika Dabrowska³, Anna Wilbrey-Clark³, Elo Madissoon¹, Zewen Kelvin Tuong⁴, Emma Dann³, Chenqu Suo⁵, Isaac Goh⁶, Masahiro Yoshida⁷, Marko Z Nikolić⁷, Sam M Janes⁷, Xiaoling He⁸, Roger A Barker⁸, Sarah A Teichmann⁹, John C Marioni¹⁰, Kerstin B Meyer³, Emma L Rawlins¹¹

Affiliations

¹ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK.
² Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1QN, UK.
³ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
⁴ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK.
⁵ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Paediatrics, Cambridge University Hospitals, Hills Road, Cambridge CB2 0 QQ, UK.
⁶ Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
⁷ Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
⁸ John van Geest Centre for Brain Repair, Department of Clinical Neurosciences and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
⁹ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, UK.
¹⁰ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
¹¹ Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: e.rawlins@gurdon.cam.ac.uk.

PMID: 36493756
DOI: 10.1016/j.cell.2022.11.005

Free article

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

Peng He et al. Cell. 2022.

Free article

. 2022 Dec 8;185(25):4841-4860.e25.

doi: 10.1016/j.cell.2022.11.005.

Authors

Affiliations

¹ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK.
² Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1QN, UK.
³ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
⁴ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Molecular Immunity Unit, University of Cambridge Department of Medicine, Cambridge, UK.
⁵ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Paediatrics, Cambridge University Hospitals, Hills Road, Cambridge CB2 0 QQ, UK.
⁶ Biosciences Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
⁷ Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK.
⁸ John van Geest Centre for Brain Repair, Department of Clinical Neurosciences and Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
⁹ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Physics, Cavendish Laboratory, University of Cambridge, Cambridge CB3 0HE, UK.
¹⁰ Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
¹¹ Wellcome Trust/CRUK Gurdon Institute, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: e.rawlins@gurdon.cam.ac.uk.

PMID: 36493756
DOI: 10.1016/j.cell.2022.11.005

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 previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface (https://lungcellatlas.org). To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models.

Keywords: differentiation; epigenetics; fibroblast; genomics; multiomic; organoids; perturbation; single-cell; spatial; transcription factor.

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Conflict of interest statement

Declaration of interests S.A.T. is a member of the Scientific Advisory Board for the following companies: Biogen, Foresite Labs, GSK, Qiagen, CRG Barcelona, Jax Labs, SciLife Lab, and Allen Institute. She is a consultant for Genentech and Roche. She is co-founder of Transition Bio and a member of the Board. Z.K.T. has received consulting fees from Synteny Biotechnologies for activities unrelated to this work.

Comment in

Empowering human lung development.
Li J, Tang N. Li J, et al. Cell Stem Cell. 2023 Jan 5;30(1):5-6. doi: 10.1016/j.stem.2022.12.012. Cell Stem Cell. 2023. PMID: 36608678

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

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

Authors

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Abstract

Conflict of interest statement

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MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials