A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

被引：825

作者：

Montoro, Daniel T. ^{[1
,2
,3
,4
,5
]}

Haber, Adam L. ^{[5
]}

Biton, Moshe ^{[5
,6
]}

Vinarsky, Vladimir ^{[1
,2
,3
,4
]}

Lin, Brian ^{[1
,2
,3
,4
]}

Birket, Susan E. ^{[7
,8
]}

Yuan, Feng ^{[9
]}

Chen, Sijia ^{[10
]}

Leung, Hui Min ^{[11
,12
]}

Villoria, Jorge ^{[1
,2
,3
,4
]}

Rogel, Noga ^{[5
]}

Burgin, Grace ^{[5
]}

Tsankov, Alexander M. ^{[5
]}

Waghray, Avinash ^{[1
,2
,3
,4
,5
]}

Slyper, Michal ^{[5
]}

Waldman, Julia ^{[5
]}

Nguyen, Lan ^{[5
]}

Dionne, Danielle ^{[5
]}

Rozenblatt-Rosen, Orit ^{[5
]}

Tata, Purushothama Rao ^{[13
,14
,15
,16
]}

Mou, Hongmei ^{[17
,18
]}

Shivaraju, Manjunatha ^{[1
,2
,3
,4
]}

Bihler, Hermann ^{[19
]}

Mense, Martin ^{[19
]}

Tearney, Guillermo J. ^{[11
,12
]}

Rowe, Steven M. ^{[7
,8
]}

Engelhardt, John F. ^{[9
]}

Regev, Aviv ^{[5
,20
,21
]}

Rajagopal, Jayaraj ^{[1
,2
,3
,4
,5
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Dept Internal Med, Pulm & Crit Care Unit, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Pediat, Pulm & Crit Care Unit, Boston, MA 02114 USA

[4] Harvard Stem Cell Inst, Cambridge, MA USA

[5] Broad Inst MIT & Harvard, Klarman Cell Observ, Cambridge, MA 02142 USA

[6] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[7] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[8] Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL USA

[9] Univ Iowa, Carver Coll Med, Dept Anat & Cell Biol, Iowa City, IA USA

[10] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, Amsterdam, Netherlands

[11] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[12] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA

[13] Duke Univ, Dept Cell Biol, Durham, NC USA

[14] Duke Univ, Duke Canc Inst, Durham, NC USA

[15] Duke Univ, Sch Med, Dept Med, Div Pulm Crit Care, Durham, NC 27706 USA

[16] Duke Univ, Regenerat Next, Durham, NC USA

[17] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA

[18] Massachusetts Gen Hosp, Mucosal Immunol & Biol Res Ctr, Boston, MA 02114 USA

[19] Cyst Fibrosis Fdn, CFFT Lab, Lexington, MA USA

[20] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[21] MIT, Dept Biol, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

来源：

NATURE | 2018年 / 560卷 / 7718期

关键词：

MUCOCILIARY TRANSPORT; BASAL-CELLS; STEM-CELLS; RNA-SEQ; MOUSE; ALVEOLAR; PROTEIN; NICHES; MUCUS; MODEL;

D O I：

10.1038/s41586-018-0393-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：319 / +

页数：26

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