An integrated cell atlas of the lung in health and disease
Lisa Sikkema, Ciro Ramírez-Suástegui, Daniel C. Strobl, Tessa E. Gillett, Luke Zappia, Elo Madissoon, Nikolay S. Markov, Laure-Emmanuelle Zaragosi, Yuge Ji, Meshal Ansari, Marie-Jeanne Arguel, Leonie Apperloo, Martin Banchero, Christophe Bécavin, Marijn Berg, Evgeny Chichelnitskiy, Mei-i Chung, Antoine Collin, Aurore C. A. Gay, Janine Gote-Schniering, Baharak Hooshiar Kashani, Kemal Inecik, Manu Jain, Theodore S. Kapellos, Tessa M. Kole, Sylvie Leroy, Christoph H. Mayr, Amanda J. Oliver, Michael von Papen, Lance Peter, Chase J. Taylor, Thomas Walzthoeni, Chuan Xu, Linh T. Bui, Carlo De Donno, Leander Dony, Alen Faiz, Minzhe Guo, Austin J. Gutierrez, Lukas Heumos, Ni Huang, Ignacio L. Ibarra, Nathan D. Jackson, Preetish Kadur Lakshminarasimha Murthy, Mohammad Lotfollahi, Tracy Tabib, Carlos Talavera-López, Kyle J. Travaglini, Anna Wilbrey-Clark, Kaylee B. Worlock, Masahiro Yoshida, Lung Biological Network Consortium, Maarten van den Berge, Yohan Bossé, Tushar J. Desai, Oliver Eickelberg, Naftali Kaminski, Mark A. Krasnow, Robert Lafyatis, Marko Z. Nikolic, Joseph E. Powell, Jayaraj Rajagopal, Mauricio Rojas, Orit Rozenblatt-Rosen, Max A. Seibold, Dean Sheppard, Douglas P. Shepherd, Don D. Sin, Wim Timens, Alexander M. Tsankov, Jeffrey Whitsett, Yan Xu, Nicholas E. Banovich, Pascal Barbry, Thu Elizabeth Duong, Christine S. Falk, Kerstin B. Meyer, Jonathan A. Kropski, Dana Pe’er, Herbert B. Schiller, Purushothama Rao Tata, Joachim L. Schultze, Sara A. Teichmann, Alexander V. Misharin, Martijn C. Nawijn, Malte D. Luecken, Fabian J. Theis
Abstract
Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
Datasets
1. An integrated cell atlas of the human lung in health and disease (core)
Metadata
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Smooth muscle FAM83D+335 cells Subpleural fibroblasts276 cells Hematopoietic stem cells60 cells Alveolar macrophages68487 cells Goblet (nasal)35833 cells Multiciliated (non-nasal)35225 cells Monocyte-derived Mph28223 cells Classical monocytes17695 cells EC general capillary16048 cells Adventitial fibroblasts10321 cells Club (non-nasal)9955 cells Non-classical monocytes8834 cells Alveolar Mph CCL3+8065 cells EC aerocyte capillary7157 cells EC venous systemic6557 cells EC venous pulmonary6418 cells Alveolar fibroblasts5182 cells Multiciliated (nasal)4869 cells Interstitial Mph perivascular4805 cells pre-TB secretory4393 cells Lymphatic EC mature4001 cells Goblet (bronchial)1670 cells Peribronchial fibroblasts1573 cells SMG serous (nasal)1472 cells SMG serous (bronchial)1417 cells Alveolar Mph MT-positive1203 cells Alveolar Mph proliferating1061 cells AT2 proliferating976 cells Goblet (subsegmental)968 cells Lymphatic EC differentiating566 cells SM activated stress response556 cells Plasmacytoid DCs552 cells T cells proliferating500 cells Smooth muscle FAM83D+335 cells Subpleural fibroblasts276 cells Hematopoietic stem cells60 cells Lymphatic EC proliferating28 cells Airway epithelium207023 cells Alveolar epithelium70342 cells Fibroblast lineage21100 cells Submucosal Gland4700 cells Hematopoietic stem cells60 cells T cell lineage50859 cells Multiciliated lineage41098 cells Innate lymphoid cell NK16978 cells Dendritic cells10319 cells Submucosal Secretory4700 cells Lymphatic EC mature4001 cells Lymphatic EC differentiating566 cells SM activated stress response556 cells Smooth muscle FAM83D+335 cells Lymphatic EC proliferating28 cells Alveolar macrophages78816 cells Interstitial macrophages33028 cells Classical monocytes17695 cells EC general capillary16048 cells Adventitial fibroblasts10321 cells Non-classical monocytes8834 cells EC aerocyte capillary7157 cells EC venous systemic6557 cells EC venous pulmonary6418 cells Transitional Club-AT25833 cells Alveolar fibroblasts5182 cells Peribronchial fibroblasts1573 cells AT2 proliferating976 cells Plasmacytoid DCs552 cells T cells proliferating500 cells Subpleural fibroblasts276 cells Goblet (nasal)35833 cells Multiciliated (non-nasal)35225 cells Monocyte-derived Mph28223 cells Club (non-nasal)9955 cells Alveolar Mph CCL3+8065 cells Multiciliated (nasal)4869 cells Interstitial Mph perivascular4805 cells pre-TB secretory4393 cells Goblet (bronchial)1670 cells SMG serous (nasal)1472 cells SMG serous (bronchial)1417 cells Alveolar Mph MT-positive1203 cells Alveolar Mph proliferating1061 cells Goblet (subsegmental)968 cells Intracranial haemorrhage42121 cells stroke, intracranial hemorrhage28029 cells intracranial hemorrhage16382 cells anoxic brain injury10327 cells head trauma from gunshot wound4880 cells anoxic brain injury after seizure4241 cells known or suspected suicide3342 cells Intracerebral hemorrhage2322 cells Banovich_Kropski_2020121894 cells Barbry_Leroy_202074487 cells Misharin_Budinger_201841220 cells Jain_Misharin_2021_10Xv233135 cells Seibold_2020_10Xv321466 cells Lafyatis_Rojas_2019_10Xv221260 cells Jain_Misharin_2021_10Xv112422 cells Teichmann_Meyer_201912231 cells Seibold_2020_10Xv212127 cells Lafyatis_Rojas_2019_10Xv12921 cells Healthy (tumor adjacent)60982 cells european/asian11725 cells Proliferating cells1812 cells Airway epithelium204889 cells Alveolar epithelium67784 cells Fibroblast lineage20549 cells Submucosal Gland6988 cells Megakaryocytic and erythroid11 cells T cell lineage43117 cells Multiciliated lineage42295 cells Innate lymphoid cell NK13927 cells Dendritic cells7813 cells Submucosal Secretory6988 cells Airway smooth muscle693 cells Vascular smooth muscle468 cells Bronchial Vessel 1455 cells Bronchial Vessel 2235 cells KRT5- KRT17+ epithelial11 cells Mesothelial DEFB4A10 cells Alveolar macrophages62343 cells Macrophages MARCO-26665 cells KRT8 high basal10754 cells EC aerocyte capillary10062 cells Classical monocytes9835 cells Interstitial macrophages8892 cells Basal proliferating7592 cells Macrophages SPP1 high5832 cells Alveolar fibroblasts4070 cells Adventitial fibroblasts3651 cells Mucous ciliated3523 cells AT2 homeostatic2602 cells Transitional AT21406 cells Non-classical monocytes1341 cells Proteasomal basal1219 cells Intermediate monocytes1171 cells Fibroblasts PLIN2+952 cells Signaling alveolar AT2669 cells EC capillary intermediate 1628 cells Plasmacytoid DCs510 cells Mph proliferating480 cells EC capillary intermediate 2464 cells EC venous systemic456 cells Subpleural fibroblasts436 cells Activated myofibroblasts312 cells TREM2+ Dendritic159 cells Fibroblasts WIF1+ CHRM2+150 cells Regulatory T cells131 cells SMG MUC5Blow DEFB1126 cells Basal KRT13 cornified103 cells NKT cells proliferating101 cells T cells proliferating46 cells SMG myoepithelial41 cells Multiciliated (non-nasal)8130 cells Interstitial Mph perivascular4142 cells Multiciliated (nasal)2889 cells Alveolar Mph activated IFI271844 cells CD8 T cells naive1411 cells Alveolar Mph CCL3+940 cells Monocyte-derived Mph363 cells Interstitial Mph FPR3+302 cells Interstitial Mph CCL3+300 cells CD4 T cells naive288 cells Interstitial Mph AXL+261 cells OLR1+ Classical Monocyte207 cells Alveolar Mph FN1+200 cells Interstitial Mph IDO1+77 cells Correctly annotated239862 cells Underannotated163227 cells Homo_sapiens.GRCh38.84560763 cells Homo_sapiens.GRCh38.9324181 cells T cell lineage43117 cells Fibroblast lineage20549 cells Dendritic cells7813 cells Submucosal Secretory6988 cells Proliferating cells1812 cells Bronchial Vessel 1455 cells Bronchial Vessel 2235 cells KRT5- KRT17+ epithelial11 cells Illumina NovaSeq 6000199172 cells Illumina HiSeq 4000159395 cells Illumina NextSeq 50098668 cells Illumina NovaSeq 6000 S457225 cells Illumina NovaSeq 6000 S141001 cells Illumina NovaSeq 6000 S221371 cells Illumina NovaSeq 6000; Illumina HiSeq 40005815 cells Illumina NovaSeq 6000 SP1920 cells Banovich_Kropski_2020121894 cells Barbry_Leroy_202074487 cells Jain_Misharin_202145557 cells Misharin_Budinger_201841220 cells Lafyatis_Rojas_201924181 cells Teichmann_Meyer_201912231 cells alive_healthy190446 cells Collagenase D + DNAse224250 cells Dispase + collagenase121894 cells Cold protease 1h120044 cells Collagenase + Elastase + DNAse60982 cells Cold protease overnight33593 cells Collagenase A + DNAse24181 cells parenchyma lower lobe118634 cells inferior turbinate78279 cells lobular bronchi74464 cells parenchyma upper lobe61735 cells distal lobular airways27543 cells parenchyma right middle lobe18541 cells left or right main bronchus9417 cells segmental bronchi7769 cells parenchyma left lower lobe65053 cells inferior turbinate right nostril53378 cells parenchyma right upper lobe29677 cells parenchyma left upper lobe26135 cells distal airways middle right lobe16227 cells parenchyma right lower lobe8112 cells inferior turbinate left nostril7122 cells lobular bronchi upper left lobe7049 cells lobular bronchi lower right lobe5056 cells distal airways lower right lobe4081 cells lobular bronchi lower left lobe3411 cells lobular bronchi upper right lobe3142 cells distal airways upper left lobe2773 cells distal airways upper right lobe2477 cells distal airways lower left lobe1985 cells surgical_resection60982 cells respiratory basal cell80113 cells alveolar macrophage78816 cells type II pneumocyte62405 cells nasal mucosa goblet cell35833 cells ciliated columnar cell of tracheobronchial tree35225 cells CD8-positive, alpha-beta T cell29074 cells elicited macrophage28223 cells capillary endothelial cell23205 cells CD4-positive, alpha-beta T cell21285 cells classical monocyte17695 cells natural killer cell16978 cells vein endothelial cell12975 cells alveolar type 2 fibroblast cell10321 cells CD1c-positive myeloid dendritic cell9133 cells non-classical monocyte8834 cells type I pneumocyte7937 cells pulmonary artery endothelial cell7391 cells multi-ciliated epithelial cell5873 cells alveolar type 1 fibroblast cell5182 cells lung macrophage4805 cells respiratory hillock cell4600 cells endothelial cell of lymphatic vessel4595 cells epithelial cell of lower respiratory tract4393 cells tracheobronchial smooth muscle cell2996 cells bronchial goblet cell1670 cells bronchus fibroblast of lung1573 cells serous secreting cell1472 cells epithelial cell of alveolus of lung1440 cells tracheobronchial serous cell1417 cells tracheobronchial goblet cell968 cells myofibroblast cell716 cells smooth muscle cell556 cells plasmacytoid dendritic cell552 cells mucus secreting cell537 cells conventional dendritic cell322 cells mesothelial cell230 cells brush cell of trachebronchial tree165 cells lung neuroendocrine cell159 cells hematopoietic stem cell60 cells lung parenchyma333468 cells respiratory airway173197 cells European,Asian11725 cells Pacific Islander2232 cells sixth decade human stage74309 cells 25-year-old human stage49574 cells 30-year-old human stage35652 cells 46-year-old human stage28792 cells 52-year-old human stage28029 cells 55-year-old human stage25789 cells 51-year-old human stage24667 cells 27-year-old human stage23001 cells seventh decade human stage22321 cells 57-year-old human stage20466 cells fifth decade human stage17786 cells 35-year-old human stage17711 cells 29-year-old human stage17533 cells 41-year-old human stage15388 cells 49-year-old human stage14613 cells 64-year-old human stage11598 cells 23-year-old human stage11591 cells 38-year-old human stage9406 cells 34-year-old human stage9134 cells 59-year-old human stage8099 cells 47-year-old human stage8016 cells 24-year-old human stage7543 cells 75-year-old human stage7523 cells 62-year-old human stage7286 cells 33-year-old human stage6816 cells 31-year-old human stage6389 cells 37-year-old human stage6255 cells 66-year-old human stage6114 cells 26-year-old human stage6001 cells 63-year-old human stage5390 cells 21-year-old human stage4880 cells 53-year-old human stage4592 cells 69-year-old human stage4305 cells 22-year-old human stage4241 cells 54-year-old human stage4061 cells fourth decade human stage3771 cells 18-year-old human stage3272 cells 68-year-old human stage2626 cells 36-year-old human stage2542 cells 10-year-old human stage2232 cells 44-year-old human stage2230 cells 56-year-old human stage2217 cells 40-year-old human stage1739 cells 61-year-old human stage1649 cells 58-year-old human stage1605 cells 42-year-old human stage1411 cells 76-year-old human stage704 cells 71-year-old human stage601 cells 15-year-old human stage47 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/6f6d381a-7701-4781-935c-db10d30de293
Alias names
HLCA, PMID37291214, PMC10287567
Cite this study
Sikkema, L., Ramírez-Suástegui, C., Strobl, D.C., Gillett, T.E., Zappia, L., Madissoon, E., Markov, N.S., Zaragosi, L.E., Ji, Y., Ansari, M. and Arguel, M.J., 2023. An integrated cell atlas of the lung in health and disease. Nature Medicine, 29(6), pp.1563-1577. https://doi.org/10.1038/s41591-023-02327-2
