Smoking shifts human small airway epithelium club cells toward a lesser differentiated population

Abstract The club cell, a small airway epithelial (SAE) cell, plays a central role in human lung host defense. We hypothesized that subpopulations of club cells with distinct functions may exist. The SAE of healthy nonsmokers and healthy cigarette smokers were evaluated by single-cell RNA sequencing...

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Autores principales:	Mahboubeh R. Rostami, Michelle G. LeBlanc, Yael Strulovici-Barel, Wulin Zuo, Jason G. Mezey, Sarah L. O’Beirne, Robert J. Kaner, Philip L. Leopold, Ronald G. Crystal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/08d73db7b3394c4286f74267ce717330
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spelling	oai:doaj.org-article:08d73db7b3394c4286f74267ce7173302021-12-02T17:19:44ZSmoking shifts human small airway epithelium club cells toward a lesser differentiated population10.1038/s41525-021-00237-12056-7944https://doaj.org/article/08d73db7b3394c4286f74267ce7173302021-09-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00237-1https://doaj.org/toc/2056-7944Abstract The club cell, a small airway epithelial (SAE) cell, plays a central role in human lung host defense. We hypothesized that subpopulations of club cells with distinct functions may exist. The SAE of healthy nonsmokers and healthy cigarette smokers were evaluated by single-cell RNA sequencing, and unsupervised clustering revealed subpopulations of SCGCB1A1+KRT5loMUC5AC− club cells. Club cell heterogeneity was supported by evaluations of SAE tissue sections, brushed SAE cells, and in vitro air–liquid interface cultures. Three subpopulations included: (1) progenitor; (2) proliferating; and (3) effector club cells. The progenitor club cell population expressed high levels of mitochondrial, ribosomal proteins, and KRT5 relative to other club cell populations and included a differentiation branch point leading to mucous cell production. The small proliferating population expressed high levels of cyclins and proliferation markers. The effector club cell cluster expressed genes related to host defense, xenobiotic metabolism, and barrier functions associated with club cell function. Comparison of smokers vs. nonsmokers demonstrated that smoking limited the extent of differentiation of all three subclusters and altered SAM pointed domain-containing Ets transcription factor (SPDEF)-regulated transcription in the effector cell population leading to a change in the location of the branch point for mucous cell production, a potential explanation for the concomitant reduction in effector club cells and increase in mucous cells in smokers. These observations provide insights into both the makeup of human SAE club cell subpopulations and the smoking-induced changes in club cell biology.Mahboubeh R. RostamiMichelle G. LeBlancYael Strulovici-BarelWulin ZuoJason G. MezeySarah L. O’BeirneRobert J. KanerPhilip L. LeopoldRonald G. CrystalNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Mahboubeh R. Rostami Michelle G. LeBlanc Yael Strulovici-Barel Wulin Zuo Jason G. Mezey Sarah L. O’Beirne Robert J. Kaner Philip L. Leopold Ronald G. Crystal Smoking shifts human small airway epithelium club cells toward a lesser differentiated population
description	Abstract The club cell, a small airway epithelial (SAE) cell, plays a central role in human lung host defense. We hypothesized that subpopulations of club cells with distinct functions may exist. The SAE of healthy nonsmokers and healthy cigarette smokers were evaluated by single-cell RNA sequencing, and unsupervised clustering revealed subpopulations of SCGCB1A1+KRT5loMUC5AC− club cells. Club cell heterogeneity was supported by evaluations of SAE tissue sections, brushed SAE cells, and in vitro air–liquid interface cultures. Three subpopulations included: (1) progenitor; (2) proliferating; and (3) effector club cells. The progenitor club cell population expressed high levels of mitochondrial, ribosomal proteins, and KRT5 relative to other club cell populations and included a differentiation branch point leading to mucous cell production. The small proliferating population expressed high levels of cyclins and proliferation markers. The effector club cell cluster expressed genes related to host defense, xenobiotic metabolism, and barrier functions associated with club cell function. Comparison of smokers vs. nonsmokers demonstrated that smoking limited the extent of differentiation of all three subclusters and altered SAM pointed domain-containing Ets transcription factor (SPDEF)-regulated transcription in the effector cell population leading to a change in the location of the branch point for mucous cell production, a potential explanation for the concomitant reduction in effector club cells and increase in mucous cells in smokers. These observations provide insights into both the makeup of human SAE club cell subpopulations and the smoking-induced changes in club cell biology.
format	article
author	Mahboubeh R. Rostami Michelle G. LeBlanc Yael Strulovici-Barel Wulin Zuo Jason G. Mezey Sarah L. O’Beirne Robert J. Kaner Philip L. Leopold Ronald G. Crystal
author_facet	Mahboubeh R. Rostami Michelle G. LeBlanc Yael Strulovici-Barel Wulin Zuo Jason G. Mezey Sarah L. O’Beirne Robert J. Kaner Philip L. Leopold Ronald G. Crystal
author_sort	Mahboubeh R. Rostami
title	Smoking shifts human small airway epithelium club cells toward a lesser differentiated population
title_short	Smoking shifts human small airway epithelium club cells toward a lesser differentiated population
title_full	Smoking shifts human small airway epithelium club cells toward a lesser differentiated population
title_fullStr	Smoking shifts human small airway epithelium club cells toward a lesser differentiated population
title_full_unstemmed	Smoking shifts human small airway epithelium club cells toward a lesser differentiated population
title_sort	smoking shifts human small airway epithelium club cells toward a lesser differentiated population
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/08d73db7b3394c4286f74267ce717330
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Smoking shifts human small airway epithelium club cells toward a lesser differentiated population

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