Format

Send to

Choose Destination
Nature. 2018 Aug;560(7720):649-654. doi: 10.1038/s41586-018-0449-8. Epub 2018 Aug 22.

Allergic inflammatory memory in human respiratory epithelial progenitor cells.

Ordovas-Montanes J1,2,3,4,5,6, Dwyer DF7,8, Nyquist SK1,2,3,4,5,9,10, Buchheit KM7,8, Vukovic M1,2,3,4,5, Deb C1,2,3,4,5, Wadsworth MH 2nd1,2,3,4,5, Hughes TK1,2,3,4,5, Kazer SW1,2,3,4,5, Yoshimoto E7,8, Cahill KN7,8, Bhattacharyya N8,11, Katz HR7,8, Berger B10,12,13, Laidlaw TM7,8, Boyce JA7,8, Barrett NA14,15, Shalek AK16,17,18,19,20,21.

Author information

1
Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA.
2
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
3
Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
6
Division of Infectious Diseases and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA.
7
Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.
8
Department of Medicine, Harvard Medical School, Boston, MA, USA.
9
Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
10
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
11
Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.
12
Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA.
13
Harvard-MIT Division of Health Sciences & Technology, Cambridge, MA, USA.
14
Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA. nbarrett@bwh.harvard.edu.
15
Department of Medicine, Harvard Medical School, Boston, MA, USA. nbarrett@bwh.harvard.edu.
16
Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu.
17
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu.
18
Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. shalek@mit.edu.
19
Broad Institute of MIT and Harvard, Cambridge, MA, USA. shalek@mit.edu.
20
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. shalek@mit.edu.
21
Harvard-MIT Division of Health Sciences & Technology, Cambridge, MA, USA. shalek@mit.edu.

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.

PMID:
30135581
PMCID:
PMC6133715
DOI:
10.1038/s41586-018-0449-8
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center