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 airway2,3,4. 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 disease7,8,9, 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.
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We thank S.L. Carroll for technical support with Seq-Well experiments; H. Raff for RNA extraction; J. Lai for histology; A. Chicoine of the Brigham and Women’s Human Immunology Flow Core for assistance with isolating cells; L. Ludwig, J. Hammelman and J. Buenrostro for advice on reagents and analysis for ATAC-seq; D. Lingwood, U.H. von Andrian, B. Walker, S. Pillai, N. Yosef, S. Rakoff-Nahoum, S. Beyaz, C. Borges, M.B. Cole, N. Yosef, R. Satija and C. Bingle for discussions and comments on the manuscript; Shalek Laboratory members for experimental and computational advice; and M. Morrison for administrative support. A.K.S. was supported by the Searle Scholars Program, the Beckman Young Investigator Program, the Pew-Stewart Scholars, a Sloan Fellowship in Chemistry, NIH grants 1DP2OD020839, 2U19AI089992, 1U54CA217377, P01AI039671, 5U24AI118672, 2RM1HG006193, 1R33CA202820, 2R01HL095791, 1R01AI138546, 1R01HL126554, 1R01DA046277, 2R01HL095791, and Bill and Melinda Gates Foundation grants OPP1139972 and BMGF OPP1116944; N.A.B. by NIH R01HL120952 and Steven and Judy Kaye Young Innovators Award; T.M.L. by NIH R01HL128241; J.A.B. by NIH U19AI095219, R01AI078908, R01AI136041, R01HLI136209; D.F.D. by T32AI007306 (to J.A.B.); K.M.B. by NIH AADCRC Opportunity Fund Award U19AI070535; and K.N.C by NIH K23AI118804. S.K.N. was supported by NIH 2R01GM081871-09 to B.B. Support was also provided from the Koch Institute Support (core) Grant P30-CA14051 from the NCI, and Ragon Institute NIH-funded Centers for AIDS Research (P30 AI060354, Harvard University Center for AIDS Research), supported by NIH co-funding and participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR. J.O.M. is a HHMI Damon Runyon Cancer Research Foundation Fellow (DRG-2274-16), and thanks S. Montanes-Ordovas for encouraging him to work on human allergic disease.
Nature thanks R. Schleimer and the other anonymous reviewer(s) for their contribution to the peer review of this work.