Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA, USA.
Nature. 2018 Aug;560(7718):319-324. doi: 10.1038/s41586-018-0393-7. Epub 2018 Aug 1.
The airways of the lung are the primary sites of disease in asthma and cystic fibrosis. Here we study the cellular composition and hierarchy of the mouse tracheal epithelium by single-cell RNA-sequencing (scRNA-seq) and in vivo lineage tracing. We identify a rare cell type, the Foxi1 pulmonary ionocyte; functional variations in club cells based on their location; a distinct cell type in high turnover squamous epithelial structures that we term 'hillocks'; and disease-relevant subsets of tuft and goblet cells. We developed 'pulse-seq', combining scRNA-seq and lineage tracing, to show that tuft, neuroendocrine and ionocyte cells are continually and directly replenished by basal progenitor cells. Ionocytes are the major source of transcripts of the cystic fibrosis transmembrane conductance regulator in both mouse (Cftr) and human (CFTR). Knockout of Foxi1 in mouse ionocytes causes loss of Cftr expression and disrupts airway fluid and mucus physiology, phenotypes that are characteristic of cystic fibrosis. By associating cell-type-specific expression programs with key disease genes, we establish a new cellular narrative for airways disease.
肺部的气道是哮喘和囊性纤维化疾病的主要发生部位。在这里，我们通过单细胞 RNA 测序（scRNA-seq）和体内谱系追踪研究了小鼠气管上皮细胞的组成和层次结构。我们鉴定出一种罕见的细胞类型，Foxi1 肺离子细胞；基于位置的 club 细胞的功能变化；在高转化鳞状上皮结构中存在一种独特的细胞类型，我们称之为“丘”；以及与疾病相关的微绒毛和杯状细胞亚群。我们开发了“脉冲测序”（pulse-seq），将 scRNA-seq 和谱系追踪相结合，表明微绒毛、神经内分泌和离子细胞可通过基底祖细胞持续和直接补充。离子细胞是小鼠（Cftr）和人类（CFTR）中囊性纤维化跨膜电导调节剂转录本的主要来源。在小鼠离子细胞中敲除 Foxi1 会导致 Cftr 表达的丧失，并破坏气道液和粘液生理学，这些表型是囊性纤维化的特征。通过将细胞类型特异性表达程序与关键疾病基因相关联，我们为气道疾病建立了一个新的细胞叙述。
