A single-cell atlas of the human healthy airways
Open accessAbstract
Rationale: The respiratory tract constitutes an elaborated line of defense based on a unique cellular ecosystem. Single-cell profiling methods enable the investigation of cell population distributions and transcriptional changes along the airways. Methods: We have explored cellular heterogeneity of the human airway epithelium in 10 healthy living volunteers by single-cell RNA profiling. 77,969 cells were collected by bronchoscopy at 35 distinct locations, from the nose to the 12 th division of the airway tree. Results: The resulting atlas is composed of a high percentage of epithelial cells (89.1%), but also immune (6.2%) and stromal (4.7%) cells with peculiar cellular proportions in different sites of the airways. It reveals differential gene expression between identical cell types (suprabasal, secretory, and multiciliated cells) from the nose ( MUC4 , PI3 , SIX3 ) and tracheobronchial ( SCGB1A1 , TFF3 ) airways. By contrast, cell-type specific gene expression was stable across all tracheobronchial samples. Our atlas improves the description of ionocytes, pulmonary neuro-endocrine (PNEC) and brush cells, which are likely derived from a common population of precursor cells. We also report a population of KRT13 positive cells with a high percentage of dividing cells which are reminiscent of “hillock” cells previously described in mouse. Conclusions: Robust characterization of this unprecedented large single-cell cohort establishes an important resource for future investigations. The precise description of the continuum existing from nasal epithelium to successive divisions of lung airways and the stable gene expression profile of these regions better defines conditions under which relevant tracheobronchial proxies of human respiratory diseases can be developed.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Analyzed samples in prior human upper airway scSeq datasets did not include any olfactory sensory neurons or sustentacular cells, indicating that tissue sampling did not include the olfactory epithelium.
“However, analyzed samples in these datasets did not include any OSNs or sustentacular cells, indicating that tissue sampling in these experiments did not include the OE (41, 42).”
From Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia (2020) · cites this paper as [41]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Part of this paper’s reference list could not be split into single entries.
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286 · see citing works
Tissue-based map of the human proteome
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015) · Science · doi:10.1126/science.1260419 · Cited by 15,286 · see citing works
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · see citing works
SCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881 · see citing works
Scenic: single-cell regulatory network inference and clustering.
Aibar, S., González-Blas, C. B., Moerman, T., Huynh-Thu, V. A., Imrichova, H., Hulselmans, G., Rambow, F., Marine, J.-C., Geurts, P., Aerts, J., et al. (2017) · Nature Methods · doi:10.1038/nmeth.4463 · Cited by 6,520 · see citing works
McCarthy, D. J., Chen, Y., & Smyth, G. K. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks042 · Cited by 5,195 · see citing works
Molecular Architecture of the Mouse Nervous System
Zeisel, A., Hochgerner, H., Lönnerberg, P., Johnsson, A., Memic, F., van der Zwan, J., Häring, M., Braun, E., Borm, L. E., La Manno, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.021 · Cited by 2,995 · see citing works
HCA Lung Biological Network, Sungnak, W., Huang, N., Bécavin, C., Berg, M., Queen, R., Litvinukova, M., Talavera-López, C., Maatz, H., Reichart, D., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0868-6 · Cited by 2,501 · see citing works
Self-citationBatch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors
Haghverdi, L., Lun, A. T. L., Morgan, M. D., & Marioni, J. C. (2018) · Nature Biotechnology · doi:10.1038/nbt.4091 · Cited by 2,416 · see citing works
Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis
Levine, J. H., Simonds, E. F., Bendall, S. C., Davis, K. L., Amir, E.-A. D., Tadmor, M. D., Litvin, O., Fienberg, H. G., Jager, A., Zunder, E. R., et al. (2015) · Cell · doi:10.1016/j.cell.2015.05.047 · Cited by 2,303 · see citing works
Self-citationZiegler, C. G. K., Allon, S. J., Nyquist, S. K., Mbano, I. M., Miao, V. N., Tzouanas, C. N., Cao, Y., Yousif, A. S., Bals, J., Hauser, B. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.035 · Cited by 2,284 · see citing works
Self-citationWolf, F. A., Hamey, F. K., Plass, M., Solana, J., Dahlin, J. S., Göttgens, B., Rajewsky, N., Simon, L., & Theis, F. J. (2019) · Genome Biology · doi:10.1186/s13059-019-1663-x · Cited by 1,698 · see citing works
A revised airway epithelial hierarchy includes CFTR-expressing ionocytes
Montoro, D. T., Haber, A. L., Biton, M., Vinarsky, V., Lin, B., Birket, S. E., Yuan, F., Chen, S., Leung, H. M., Villoria, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0393-7 · Cited by 1,206 · see citing works
Reyfman, P. A., Walter, J. M., Joshi, N., Anekalla, K. R., McQuattie-Pimentel, A. C., Chiu, S., Fernandez, R., Akbarpour, M., Chen, C.-I., Ren, Z., et al. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201712-2410oc · Cited by 1,203 · see citing works
Sungnak, W., Huang, N., Bécavin, C., & Berg, M. (2020) · PubMed · Cited by 1,196 · see citing works
Pooling across cells to normalize single-cell RNA sequencing data with many zero counts
L. Lun, A. T., Bach, K., & Marioni, J. C. (2016) · Genome Biology · doi:10.1186/s13059-016-0947-7 · Cited by 1,108 · see citing works
A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte
Plasschaert, L. W., Žilionis, R., Choo-Wing, R., Savova, V., Knehr, J., Roma, G., Klein, A. M., & Jaffe, A. B. (2018) · Nature · doi:10.1038/s41586-018-0394-6 · Cited by 1,047 · see citing works
Rock, J. R., Barkauskas, C. E., Cronce, M. J., Xue, Y., Harris, J. R., Liang, J., Noble, P. W., & Hogan, B. L. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117988108 · Cited by 1,033 · see citing works
A cellular census of human lungs identifies novel cell states in health and in asthma
Vieira Braga, F. A., Kar, G., Berg, M., Carpaij, O. A., Polanski, K., Simon, L. M., Brouwer, S., Gomes, T., Hesse, L., Jiang, J., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0468-5 · Cited by 896 · see citing works
An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics
Angelidis, I., Simon, L. M., Fernandez, I. E., Strunz, M., Mayr, C. H., Greiffo, F. R., Tsitsiridis, G., Ansari, M., Graf, E., Strom, T.-M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08831-9 · Cited by 637 · see citing works
Ruiz García, S., Deprez, M., Lebrigand, K., Cavard, A., Paquet, A., Arguel, M.-J., Magnone, V., Truchi, M., Caballero, I., Leroy, S., et al. (2019) · Development · doi:10.1242/dev.177428 · Cited by 297 · see citing works
Self-citationNumber and Proliferation of Basal and Parabasal Cells in Normal Human Airway Epithelium
Boers, J. E., Ambergen, A. W., & Thunnissen, E. (1998) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.157.6.9707011 · Cited by 287 · see citing works
Samitas, Κ., Carter, A., Kariyawasam, H. H., & Xanthou, G. (2017) · Allergy · doi:10.1111/all.13373 · Cited by 270 · see citing works
Airway Gland Structure and Function
Widdicombe, J. H., & Wine, J. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00039.2014 · Cited by 206 · see citing works
Pardo–Saganta, A., Law, B. M., Tata, P. R., Villoria, J., Sáez, B., Mou, H., Zhao, R., & Rajagopal, J. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.01.002 · Cited by 202 · see citing works
Nasal Epithelial Cells as Surrogates for Bronchial Epithelial Cells in Airway Inflammation Studies
McDougall, C. M., Blaylock, M. G., Douglas, J. G., Brooker, R., Helms, P. J. B., & Walsh, G. M. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2007-0325oc · Cited by 195 · see citing works
Notch3-Jagged signaling controls the pool of undifferentiated airway progenitors
Mori, M., Mahoney, J. E., Stupnikov, M. R., Paez-Cortez, J. R., Szymaniak, A. D., Varelas, X., Herrick, D. B., Schwob, J. E., Zhang, H., & Cardoso, W. V. (2015) · Development · doi:10.1242/dev.116855 · Cited by 168 · see citing works
Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation
Rajavelu, P., Chen, G., Xu, Y. J., Kitzmiller, J. A., Korfhagen, T. R., & Whitsett, J. A. (2015) · Journal of Clinical Investigation · doi:10.1172/jci79422 · Cited by 159 · see citing works
The homeobox gene Otx2 in development and disease
Béby, F., & Lamonerie, T. (2013) · Experimental Eye Research · doi:10.1016/j.exer.2013.03.007 · Cited by 148 · see citing works
The Development of Large and Small Airways
Jeffery, P. K. (1998) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm.157.5.rsaa-1 · Cited by 141 · see citing works
Foxa3 Induces Goblet Cell Metaplasia and Inhibits Innate Antiviral Immunity
Chen, G., Korfhagen, T. R., Karp, C. L., Impey, S., Xu, Y. J., Randell, S. H., Kitzmiller, J. A., Maeda, Y., Haitchi, H. M., Sridharan, A., et al. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201306-1181oc · Cited by 139 · see citing works
The Contribution of the Neural Crest to the Vertebrate Body
Dupin, É., Creuzet, S., & Douarin, N. M. L. (2006) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-46954-6_6 · Cited by 134 · see citing works
Sinn, R., & Wittbrodt, J. (2013) · Mechanisms of Development · doi:10.1016/j.mod.2013.05.001 · Cited by 125 · see citing works
CDC20B is required for deuterosome-mediated centriole production in multiciliated cells
Revinski, D. R., Zaragosi, L., Boutin, C., García, S. R., Deprez, M., Thomé, V., Rosnet, O., Gay, A.-S., Mercey, O., Paquet, A. C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06768-z · Cited by 87 · see citing works
Self-citationExpression, regulation, and function of the SPR family of proteins
Tesfaigzi, Y., & Carlson, D. M. (1999) · Cell Biochemistry and Biophysics · doi:10.1007/bf02738069 · Cited by 84 · see citing works
An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomicsPreprint
Angelidis, I., Simon, L. M., Fernandez, I. E., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/351353 · Cited by 71 · see citing works
Development and distribution of mucous glands in the fœtal human trachea
Thurlbeck, W. M., Benjamin, B., & REID, L. M. (1961) · British Journal of Diseases of the Chest · doi:10.1016/s0007-0971(61)80002-8 · Cited by 59 · see citing works
Mihaylova, V. T., Kong, Y., Fedorova, O., Sharma, L., Dela Cruz, C. S., Pyle, A. M., Iwasaki, A., & Foxman, E. F. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.033 · Cited by 59 · see citing works
Six3 is required for ependymal cell maturation
Lavado, A., & Oliver, G. C. (2011) · Development · doi:10.1242/dev.067470 · Cited by 54 · see citing works
Roberts, N., Mubarak, R. A., Francisco, D., Kraft, M., & Chu, H. W. (2018) · Clinical and Translational Medicine · doi:10.1186/s40169-018-0189-2 · Cited by 52 · see citing works
Champliaud, M.-F., Burgeson, R. E., Jin, W. W., et al. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.47.31547 · Cited by 45 · see citing works
The “one airway, one disease” concept in light of Th2 inflammation
Giovannini‐Chami, L., Paquet, A. C., Sanfiorenzo, C., Pons, N., Cazareth, J., Magnone, V., Lebrigand, K., Chevalier, B., Vallauri, A., Julia, V., et al. (2018) · European Respiratory Journal · doi:10.1183/13993003.00437-2018 · Cited by 45 · see citing works
Self-citationTakahashi, Y., Kitajima, S., Inoue, T., et al. (2005) · Development · doi:10.1242/dev.01597 · Cited by 44 · see citing works
Neural Crest and Placode Contributions to Olfactory Development
Suzuki, J., & Osumi, N. (2015) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2014.11.010 · Cited by 41 · see citing works
Gene network approach reveals co-expression patterns in nasal and bronchial epithelium
Imkamp, K., Bernal, V., Grzegorczyk, M. A., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-50963-x · Cited by 28 · see citing works
Development of the mucous glands in the human main bronchus.
Tos, M. (1968) · PubMed · Cited by 27 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
HCA Lung Biological Network, Sungnak, W., Huang, N., Bécavin, C., Berg, M., Queen, R., Litvinukova, M., Talavera-López, C., Maatz, H., Reichart, D., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0868-6 · Cited by 2,501 · see citing works
Self-citationSARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract
Hou, Y. J., Okuda, K., Edwards, C. E., Martinez, D. R., Asakura, T., Dinnon, K. H., Kato, T., Lee, R. E., Yount, B. L., Mascenik, T. M., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.042 · Cited by 1,488 · see citing works
Brann, D. H., Tsukahara, T., Weinreb, C., Lipovsek, M., Van den Berge, K., Gong, B., Chance, R., Macaulay, I. C., Chou, H.-J., Fletcher, R. B., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc5801 · Cited by 1,198 · see citing works
Transfer learning enables predictions in network biology
Theodoris, C. V., Xiao, L., Chopra, A., Chaffin, M. D., Al Sayed, Z. R., Hill, M. C., Mantineo, H., Brydon, E. M., Zeng, Z., Liu, X. S., et al. (2023) · Nature · doi:10.1038/s41586-023-06139-9 · Cited by 1,193 · see citing works
Lung adenocarcinoma promotion by air pollutants
Hill, W., Lim, E. L., Weeden, C. E., Lee, C., Augustine, M., Chen, K., Kuan, F.-C., Marongiu, F., Evans, E. J., Moore, D. A., et al. (2023) · Nature · doi:10.1038/s41586-023-05874-3 · Cited by 808 · see citing works
Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours
Gavish, A., Tyler, M., Greenwald, A. C., Hoefflin, R., Simkin, D., Tschernichovsky, R., Galili Darnell, N., Somech, E., Barbolin, C., Antman, T., et al. (2023) · Nature · doi:10.1038/s41586-023-06130-4 · Cited by 556 · see citing works
Local and systemic responses to SARS-CoV-2 infection in children and adults
Yoshida, M., Worlock, K. B., Huang, N., Lindeboom, R. G. H., Butler, C. R., Kumasaka, N., Dominguez Conde, C., Mamanova, L., Bolt, L., Richardson, L., et al. (2022) · Nature · doi:10.1038/s41586-021-04345-x · Cited by 365 · see citing works
A spatially resolved atlas of the human lung characterizes a gland-associated immune niche
Madissoon, E., Oliver, A. J., Kleshchevnikov, V., Wilbrey-Clark, A., Polanski, K., Richoz, N., Ribeiro Orsi, A., Mamanova, L., Bolt, L., Elmentaite, R., et al. (2023) · Nature Genetics · doi:10.1038/s41588-022-01243-4 · Cited by 219 · see citing works
Motile cilia and airway disease
Legendre, M., Zaragosi, L.-E., & Mitchison, H. M. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.11.007 · Cited by 175 · see citing works
Self-citationLungMAP Portal Ecosystem: Systems-level Exploration of the Lung
Gaddis, N., Fortriede, J., Guo, M., Bardes, E. E., Kouril, M., Tabar, S., Burns, K., Ardini-Poleske, M. E., Loos, S., Schnell, D., et al. (2024) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2022-0165oc · Cited by 62 · see citing works
- Authors
- Deprez, M., Zaragosi, L.-E., Truchi, M., Garcia, S. R., Arguel, M.-J., Lebrigand, K., Paquet, A., Pee’r, D., Marquette, C.-H., Leroy, S., & Barbry, P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Barbry, Pascal
- ORCID
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- openRxiv
- Published
- 2019-12-23
- Volume
- 202
- Issue
- 12
- Pages
- 1636-1645
- ISSN
- 1073-449X (ISSN-L)
- OpenAlex
- W3045953207
- Cited by
- 493
- References
- 47
- Citations by year
- 2026: 56 · 2025: 89 · 2024: 83 · 2023: 95 · 2022: 78 · 2021: 62 · 2020: 29 · 2019: 1
- FWCI
- 21.41
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche (ANR-19-P3IA-0002, ANR-10-INBS-0009, ANR-15-IDEX-0001, ANR-19-CE14-0027)
- Agence Nationale de Sécurité du Médicament et des Produits de Santé
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- human airway epithelium, single-cell atlas, gene expression profiling, suprabasal cells, secretory cells, multiciliated cells, ionocytes, pulmonary neuroendocrine cells, brush cells, keratin 13, squamous cells, tracheobronchial airways, nasal epithelium, MUC4, SCGB1A1, TFF3
- MeSH terms
- Adult, Aged, Aged, 80 and over, Bronchi, Cell Differentiation, Epithelial Cells, Female, Gene Expression Regulation, Humans, Male, Middle Aged, Nasal Mucosa, Stromal Cells, Cell Proliferation, Healthy Volunteers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
