Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 198, Issue 11, Pages 1375-1388Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201710-2107OC
Keywords
club cell; principal component gradient analysis; small airway epithelium
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Funding
- NIH [R01HL107882, R01HL1189541, T32HL094284]
- NIH Shared Instrumentation Grant [S10RR027699]
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027699] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL118541, R01HL107882, T32HL094284] Funding Source: NIH RePORTER
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Rationale: Little is known about human club cells, dome-shaped cells with dense cytoplasmic granules and microvilli that represent the major secretory cells of the human small airways (at least sixth-generation bronchi). Objectives: To define the ontogeny and biology of the human small airway epithelium club cell. Methods: The small airway epithelium was sampled from the normal human lung by bronchoscopy and brushing. Single-cell transcriptome analysis and air-liquid interface culture were used to assess club cell ontogeny and biology. Measurements and Main Results: We identified the club cell population by unbiased clustering using single-cell transcriptome sequencing. Principal component gradient analysis uncovered an ontologic link between KRT5 (keratin 5)(+) basal cells and SCGBIA1 (secretoglobin family 1 A member 1)(+) club cells, a hypothesis verified by demonstrating in vitro that a pure population of human KRT5(+) SCGBIA1(-) small airway epithelial basal cells differentiate into SCGBIA1(+) KRT5(-) club cells on air-liquid interface culture. Using SCGBIA1 as the marker of club cells, the single-cell analysis identified novel roles for these cells in host defense, xenobiotic metabolism, antiprotease, physical barrier function, monogenic lung disorders, and receptors for human viruses. Conclusions: These observations provide novel insights into the molecular phenotype and biologic functions of the human club cell population and identify basal cells as the human progenitor cells for dub cells.
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