Allergic inflammatory memory in human respiratory epithelial progenitor cells

Jose Ordovas-Montanes, Daniel F. Dwyer, Sarah K. Nyquist, Kathleen M. Buchheit, Marko Vukovic, Chaarushena Deb, Marc H. Wadsworth, Travis K. Hughes, Samuel W. Kazer, Eri Yoshimoto, Katherine N. Cahill, Neil Bhattacharyya, Howard R. Katz, Bonnie Berger, Tanya M. Laidlaw, Joshua A. Boyce, Nora A. Barrett () and Alex K. Shalek ()
Additional contact information
Jose Ordovas-Montanes: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Daniel F. Dwyer: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Sarah K. Nyquist: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Kathleen M. Buchheit: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Marko Vukovic: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Chaarushena Deb: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Marc H. Wadsworth: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Travis K. Hughes: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Samuel W. Kazer: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology
Eri Yoshimoto: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Katherine N. Cahill: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Neil Bhattacharyya: Harvard Medical School
Howard R. Katz: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Bonnie Berger: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology
Tanya M. Laidlaw: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Joshua A. Boyce: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Nora A. Barrett: Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital
Alex K. Shalek: Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology

Nature, 2018, vol. 560, issue 7720, 649-654

Abstract: Abstract Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases1. Specialized subsets of epithelial cells—including secretory and ciliated cells—differentiate from basal stem cells to collectively protect the upper airway2–4. Allergic inflammation can develop from persistent activation5 of type 2 immunity6 in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps7. Basal cell hyperplasia is a hallmark of severe disease7–9, but it is not known how these progenitor cells2,10,11 contribute to clinical presentation and barrier tissue dysfunction in humans. Here we profile primary human surgical chronic rhinosinusitis samples (18,036 cells, n = 12) that span the disease spectrum using Seq-Well for massively parallel single-cell RNA sequencing12, report transcriptomes for human respiratory epithelial, immune and stromal cell types and subsets from a type 2 inflammatory disease, and map key mediators. By comparison with nasal scrapings (18,704 cells, n = 9), we define signatures of core, healthy, inflamed and polyp secretory cells. We reveal marked differences between the epithelial compartments of the non-polyp and polyp cellular ecosystems, identifying and validating a global reduction in cellular diversity of polyps characterized by basal cell hyperplasia, concomitant decreases in glandular cells, and phenotypic shifts in secretory cell antimicrobial expression. We detect an aberrant basal progenitor differentiation trajectory in polyps, and propose cell-intrinsic13, epigenetic14,15 and extrinsic factors11,16,17 that lock polyp basal cells into this uncommitted state. Finally, we functionally demonstrate that ex vivo cultured basal cells retain intrinsic memory of IL-4/IL-13 exposure, and test the potential for clinical blockade of the IL-4 receptor α-subunit to modify basal and secretory cell states in vivo. Overall, we find that reduced epithelial diversity stemming from functional shifts in basal cells is a key characteristic of type 2 immune-mediated barrier tissue dysfunction. Our results demonstrate that epithelial stem cells may contribute to the persistence of human disease by serving as repositories for allergic memories.

Date: 2018
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DOI: 10.1038/s41586-018-0449-8

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