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 SCGB1A1 (secretoglobin family 1A member 1)+ club cells, a hypothesis verified by demonstrating in vitro that a pure population of human KRT5+ SCGB1A1- small airway epithelial basal cells differentiate into SCGB1A1+KRT5- club cells on air-liquid interface culture. Using SCGB1A1 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 club cells.

中文翻译：

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人类小气道上皮俱乐部细胞的个体发育和生物学。

基本原理对人类棒状细胞、具有致密细胞质颗粒和微绒毛的圆顶状细胞知之甚少，这些细胞代表人类小气道（至少第六代支气管）的主要分泌细胞。目的 确定人类小气道上皮俱乐部细胞的个体发育和生物学。方法通过支气管镜检查和刷牙从正常人肺中取样小气道上皮。单细胞转录组分析和气液界面培养用于评估棒状细胞个体发育和生物学。测量和主要结果我们使用单细胞转录组测序通过无偏聚类确定了俱乐部细胞群。主成分梯度分析揭示了 KRT5（角蛋白 5）+ 基底细胞和 SCGB1A1（分泌珠蛋白家族 1A 成员 1）+ 俱乐部细胞之间的本体论联系，通过在体外证明纯人类 KRT5+ SCGB1A1- 小气道上皮基底细胞群在气-液界面培养上分化为 SCGB1A1+KRT5- 俱乐部细胞而验证的假设。使用 SCGB1A1 作为俱乐部细胞的标志物，单细胞分析确定了这些细胞在宿主防御、异生物质代谢、抗蛋白酶、物理屏障功能、单基因肺病和人类病毒受体中的新作用。结论这些观察结果为人类棒状细胞群的分子表型和生物学功能提供了新的见解，并将基底细胞鉴定为棒状细胞的人类祖细胞。使用 SCGB1A1 作为俱乐部细胞的标志物，单细胞分析确定了这些细胞在宿主防御、异生物质代谢、抗蛋白酶、物理屏障功能、单基因肺病和人类病毒受体中的新作用。结论这些观察结果为人类棒状细胞群的分子表型和生物学功能提供了新的见解，并将基底细胞鉴定为棒状细胞的人类祖细胞。使用 SCGB1A1 作为俱乐部细胞的标志物，单细胞分析确定了这些细胞在宿主防御、异生物质代谢、抗蛋白酶、物理屏障功能、单基因肺病和人类病毒受体中的新作用。结论这些观察结果为人类棒状细胞群的分子表型和生物学功能提供了新的见解，并将基底细胞鉴定为棒状细胞的人类祖细胞。