Allergic inflammatory memory in human respiratory epithelial progenitor cells
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 inflamma...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2019
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| Online Access: | https://hdl.handle.net/1721.1/122932 |
| _version_ | 1811071596576636928 |
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| author | 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 Cahill, Katherine N. Bhattacharyya, Neil Katz, Howard R. Berger Leighton, Bonnie Laidlaw, Tanya M. Boyce, Joshua A. Barrett, Nora A. Shalek, Alexander K |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science 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 Cahill, Katherine N. Bhattacharyya, Neil Katz, Howard R. Berger Leighton, Bonnie Laidlaw, Tanya M. Boyce, Joshua A. Barrett, Nora A. Shalek, Alexander K |
| author_sort | Ordovas-Montanes, Jose Manuel |
| collection | MIT |
| description | 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 |
| first_indexed | 2024-09-23T08:53:41Z |
| format | Article |
| id | mit-1721.1/122932 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:53:41Z |
| publishDate | 2019 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1229322022-09-30T11:59:14Z Allergic inflammatory memory in human respiratory epithelial progenitor cells 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 Cahill, Katherine N. Bhattacharyya, Neil Katz, Howard R. Berger Leighton, Bonnie Laidlaw, Tanya M. Boyce, Joshua A. Barrett, Nora A. Shalek, Alexander K 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 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 National Institutes of Health (U.S.) (Grant 1DP2OD020839) National Institutes of Health (U.S.) (Grant 2U19AI089992) National Institutes of Health (U.S.) (Grant 1U54CA217377) National Institutes of Health (U.S.) (Grant P01AI039671) National Institutes of Health (U.S.) (Grant 5U24AI118672) National Institutes of Health (U.S.) (Grant 2RM1HG006193) National Institutes of Health (U.S.) (Grant 1R33CA202820) National Institutes of Health (U.S.) (Grant 2R01HL095791) National Institutes of Health (U.S.) (Grant 1R01AI138546) National Institutes of Health (U.S.) (Grant 1R01HL126554) National Institutes of Health (U.S.) (Grant 1R01DA046277) National Institutes of Health (U.S.) (Grant 2R01HL095791) Bill & Melinda Gates Foundation (Grant OPP1139972) Bill & Melinda Gates Foundation (Grant OPP1116944) National Institutes of Health (U.S.) (Grant 2R01GM081871–09 ) National Cancer Institute (U.S.) (Grant P30-CA14051) National Institutes of Health (U.S.). Center for AIDS Research (Award P30 AI060354) 2019-11-14T16:48:54Z 2019-11-14T16:48:54Z 2018-08-22 2017-11-05 2019-11-07T18:12:47Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 https://hdl.handle.net/1721.1/122932 Ordovas-Montanes, Jose et al. "Allergic inflammatory memory in human respiratory epithelial progenitor cells." Nature 560, 7720 (2018): 649–654 © 2018 Springer Nature en http://dx.doi.org/10.1038/s41586-018-0449-8 Nature 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. application/pdf Springer Nature PMC |
| spellingShingle | 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 Cahill, Katherine N. Bhattacharyya, Neil Katz, Howard R. Berger Leighton, Bonnie Laidlaw, Tanya M. Boyce, Joshua A. Barrett, Nora A. Shalek, Alexander K Allergic inflammatory memory in human respiratory epithelial progenitor cells |
| title | Allergic inflammatory memory in human respiratory epithelial progenitor cells |
| title_full | Allergic inflammatory memory in human respiratory epithelial progenitor cells |
| title_fullStr | Allergic inflammatory memory in human respiratory epithelial progenitor cells |
| title_full_unstemmed | Allergic inflammatory memory in human respiratory epithelial progenitor cells |
| title_short | Allergic inflammatory memory in human respiratory epithelial progenitor cells |
| title_sort | allergic inflammatory memory in human respiratory epithelial progenitor cells |
| url | https://hdl.handle.net/1721.1/122932 |
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