Human Primary Airway Basal Cells Display a Continuum of Molecular Phases from Health to Disease in COPD

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T1 - Human Primary Airway Basal Cells Display a Continuum of Molecular Phases from Health to Disease in COPD

AU - Wijk, Sofia C

AU - Prabhala, Pavan

AU - Michaliková, Barbora

AU - Sommarin, Mikael

AU - Doyle, Alexander

AU - Lang, Stefan

AU - Kanzenbach, Karina

AU - Tufvesson, Ellen

AU - Lindstedt, Sandra

AU - Leigh, Nicholas D

AU - Karlsson, Göran

AU - Bjermer, Leif

AU - Westergren Thorsson, Gunilla

AU - Magnusson, Mattias

PY - 2021/3/31

Y1 - 2021/3/31

N2 - Airway basal cells are crucial for regeneration of the human lung airway epithelium, and are thought to be important contributors to Chronic Obstructive Pulmonary Disease (COPD) and other lung disorders. In order to reveal how basal cells contribute to disease, and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and Nerve-Growth Factor Receptor (NGFR) expression. The basal cell population was found to be molecularly and functionally heterogeneous in contrast to cultured basal cells. In addition, significant differences were found such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single cell RNA sequencing on primary basal cells from healthy donors and GOLD stage IV COPD patients, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response related genes GADD45B and AHSA1, along with genes involved in the response to hypoxia such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung.

AB - Airway basal cells are crucial for regeneration of the human lung airway epithelium, and are thought to be important contributors to Chronic Obstructive Pulmonary Disease (COPD) and other lung disorders. In order to reveal how basal cells contribute to disease, and to discover novel therapeutic targets, these basal cells need to be further characterized. In this study, we optimized a flow cytometry-based cell sorting protocol for primary human airway basal cells dependent on cell size and Nerve-Growth Factor Receptor (NGFR) expression. The basal cell population was found to be molecularly and functionally heterogeneous in contrast to cultured basal cells. In addition, significant differences were found such as KRT14 expression exclusively existing in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single cell RNA sequencing on primary basal cells from healthy donors and GOLD stage IV COPD patients, the gene expression revealed a continuum ranging from healthy basal cell signatures to diseased basal cell phenotypes. We identified several upregulated genes that may indicate COPD, such as stress response related genes GADD45B and AHSA1, along with genes involved in the response to hypoxia such as CITED2 and SOD1. Taken together, the presence of healthy basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms as well as for developing future cell-based therapies in the human lung.

U2 - 10.1165/rcmb.2020-0464OC

DO - 10.1165/rcmb.2020-0464OC

M3 - Article

C2 - 33789072

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1535-4989

ER -