Allergic inflammatory memory in human respiratory epithelial progenitor cells
Name
nihms-979718.pdf
Description
Accepted version
Size
2.79 MB
Format
Adobe PDF
Checksum (MD5)
c74f3ffea44e79600ad8faaa1f1c0693
Author(s)
Ordovas-Montanes, Jose Manuel
Dwyer, Daniel F.
Nyquist, Sarah Kate
Buchheit, Kathleen M.
Vukovic, Marko
Deb, Chaarushena
Wadsworth, Marc Havens
Hughes, Travis K.
Kazer, Samuel Weisgurt
Yoshimoto, Eri
Date Issued
August 22, 2018
Journal
Nature
Publisher
Springer Nature
Citation
Ordovas-Montanes, Jose et al. "Allergic inflammatory memory in human respiratory epithelial progenitor cells." Nature 560, 7720 (2018): 649–654 © 2018 Springer Nature
Version
Author's final manuscript
Abstract
Barrier tissue dysfunction is a fundamental feature of chronic human inflammatory diseases [superscript 1]. Specialized subsets of epithelial cells—including secretory and ciliated cells—differentiate from basal stem cells to collectively protect the upper airway [superscript 2–4]. Allergic inflammation can develop from persistent activation [superscript 5] of type 2 immunity [superscript 6] in the upper airway, resulting in chronic rhinosinusitis, which ranges in severity from rhinitis to severe nasal polyps [superscript 7]. Basal cell hyperplasia is a hallmark of severe disease [superscript 7–9], but it is not known how these progenitor cells [superscript 2,10,11] 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 sequencing [superscript 12], 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-intrinsic [superscript 13], epigenetic [superscript 14,15] and extrinsic factors [superscript 11,16,17] 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. K
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemistry
Ragon Institute of MGH, MIT and Harvard
Massachusetts Institute of Technology. Computational and Systems Biology Program
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Mathematics
Harvard University--MIT Division of Health Sciences and Technology
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/s41586-018-0449-8
