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Reduced cellular diversity and an altered basal progenitor cell state inform epithelial barrier dysfunction in human type 2 immunity

View ORCID ProfileJose Ordovas-Montanes, Daniel F. Dwyer, Sarah K. Nyquist, Kathleen M. Buchheit, Chaarushena Deb, Marc H. Wadsworth II, Travis K. Hughes, Samuel W. Kazer, Eri Yoshimoto, Neil Bhattacharyya, Howard R. Katz, Tanya M. Laidlaw, Joshua A. Boyce, Nora A. Barrett, View ORCID ProfileAlex K. Shalek
doi: https://doi.org/10.1101/218958
Jose Ordovas-Montanes
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
4Division of Infectious Diseases and Division of Gastroenterology, Boston Children’s Hospital, Boston, MA, USA
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  • ORCID record for Jose Ordovas-Montanes
Daniel F. Dwyer
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Sarah K. Nyquist
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
7Program in Computational and Systems Biology, MIT, Cambridge, MA, USA
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Kathleen M. Buchheit
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Chaarushena Deb
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Marc H. Wadsworth II
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Travis K. Hughes
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Samuel W. Kazer
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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Eri Yoshimoto
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Neil Bhattacharyya
6Department of Medicine, Harvard Medical School, Boston, MA, USA
8Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA
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Howard R. Katz
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Tanya M. Laidlaw
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Joshua A. Boyce
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Nora A. Barrett
5Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA, USA
6Department of Medicine, Harvard Medical School, Boston, MA, USA
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Alex K. Shalek
1Institute for Medical Engineering and Science (IMES) and Department of Chemistry, MIT, Cambridge, MA, USA
2Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Alex K. Shalek
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ABSTRACT

Tissue barrier dysfunction is a poorly defined feature hypothesized to drive chronic human inflammatory disease1,2. The epithelium of the upper respiratory tract represents one such barrier, responsible for separating inhaled agents, such as pathogens and allergens, from the underlying submucosa. Specialized epithelial subsets—including secretory, glandular, and ciliated cells—differentiate from basal progenitors to collectively realize this role3⇓-5. Allergic inflammation in the upper airway barrier can develop from persistent activation of Type 2 immunity (T2I), resulting in the disease spectrum known as chronic rhinosinusitis (CRS), ranging from rhinitis to severe nasal polyps6⇓-8. Whether recently identified epithelial progenitor subsets, and their differentiation trajectory, contribute to the clinical presentation and barrier dysfunction in T2I-mediated disease in humans remains unexplored3,9,10. Profiling twelve primary human samples spanning the range of clinical severity with the Seq-Well platform11 for massively-parallel single-cell RNA-sequencing (scRNA-seq), we report the first single-cell transcriptomes for human respiratory epithelial cell subsets, immune cells, and parenchymal cells (18,036 total cells) from a T2I inflammatory disease, and map key mediators. We find striking differences between non-polyp and polyp tissues within the epithelial compartments of human T2I cellular ecosystems. More specifically, across 10,383 epithelial cells, we identify a global reduction in epithelial diversity in polyps characterized by basal cell hyperplasia, a concomitant decrease in glandular and ciliated cells, and phenotypic shifts in secretory cell function. We validate these findings through flow cytometry, histology, and bulk tissue RNA-seq of an independent cohort. Furthermore, we detect an aberrant basal progenitor differentiation trajectory in polyps, and uncover cell-intrinsic and extrinsic factors that may lock polyp basal cells into an uncommitted state. Overall, our data define severe T2I barrier dysfunction as a reduction in epithelial diversity, characterized by profound functional shifts stemming from basal cell defects, and nominate a cellular mechanism for the persistence and chronicity of severe human respiratory disease.

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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 November 14, 2017.
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Reduced cellular diversity and an altered basal progenitor cell state inform epithelial barrier dysfunction in human type 2 immunity
Jose Ordovas-Montanes, Daniel F. Dwyer, Sarah K. Nyquist, Kathleen M. Buchheit, Chaarushena Deb, Marc H. Wadsworth II, Travis K. Hughes, Samuel W. Kazer, Eri Yoshimoto, Neil Bhattacharyya, Howard R. Katz, Tanya M. Laidlaw, Joshua A. Boyce, Nora A. Barrett, Alex K. Shalek
bioRxiv 218958; doi: https://doi.org/10.1101/218958
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Reduced cellular diversity and an altered basal progenitor cell state inform epithelial barrier dysfunction in human type 2 immunity
Jose Ordovas-Montanes, Daniel F. Dwyer, Sarah K. Nyquist, Kathleen M. Buchheit, Chaarushena Deb, Marc H. Wadsworth II, Travis K. Hughes, Samuel W. Kazer, Eri Yoshimoto, Neil Bhattacharyya, Howard R. Katz, Tanya M. Laidlaw, Joshua A. Boyce, Nora A. Barrett, Alex K. Shalek
bioRxiv 218958; doi: https://doi.org/10.1101/218958

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