Protective cell layers differ between upper and lower airways

Researchers observe differences in epithelial cells in cystic fibrosis patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Epithelial cells — the protective cells that line the airways — taken from people with cystic fibrosis (CF) exhibited distinct cellular and genetic features in lab cultures depending on whether they were obtained from the upper or lower airways, according to recent research.

Those differences corresponded to distinct fluid-secreting capacities in the two tissues.

Researchers believe the findings highlight unique features and demonstrate that patient cells cultured in the lab can serve as models to further “investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF,” the researchers wrote.

The study, “Exploring intrinsic variability between cultured nasal and bronchial epithelia in cystic fibrosis,” was published in Scientific Reports.

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Airway epithelial layers serve as a barrier to protect the lungs against environmental invaders, like viruses, that we breathe in. They contain various cell types, including ciliated and secretory cells that together launch a defense mechanism called mucociliary clearance.

Secretory cells are responsible for producing mucus, containing immune and detoxifying proteins, that traps a harmful invader. Ciliated cells, which contain the hairlike structures (cilia) on their surface involved in movement, work to propel the trapped pathogens out of the airways.

In CF, mutations in the CFTR gene lead to the buildup of thick, sticky mucus in the airways that damages this defense system, leading to progressive lung injury and breathing problems.

There are different types of airway epithelia throughout the respiratory tract. The nasal epithelium lines the airway passages in the nose — a part of the upper airways — and is the first line of defense against airway invaders. The bronchial epithelium is found lower in the respiratory tract where the bronchi help carry air into the lungs.

Airway epithelial cells have distinct differences

Accumulating evidence indicates these different epithelial tissues have distinct differences in terms of cell composition and genetics.

Still, “it remains unexplored whether these tissue-specific hallmarks affect nasal and bronchial epithelial cell functioning, and therefore have differential outcomes on upper and lower respiratory disease development in CF,” the researchers wrote.

As such, the team examined whether in vitro (in the lab) approaches could be developed and used to study differences in these two tissues, and how they affect epithelial cell function in CF.

Cellular and genetic makeup studied in cell cultures

Epithelial cells were obtained from children with CF and grown in cell cultures, where the scientists observed several differences in the cellular and genetic makeup of the two cell types.

While bronchial cells tended to have higher activity, or expression, of genes related to ciliated cells, nasal cells were more enriched for genes associated with goblet cells, which are secretory cells that produce the main component of mucus.

Nasal cells also had lower expression of proteins associated with the protective barriers formed by epithelia to prevent the passage of harmful substance.

“Overall, these results support the notion that nasal and bronchial epithelial cells exhibit unique cell type-specific differentiation characteristics that persists in cell culture,” the researchers wrote.

Next, the scientists developed bronchial or nasal epithelium organoids, or “mini-organs,” from the cell cultures. These three-dimensional models grown in vitro mimic the structure and function of the tissue being studied.

Results showed that the two types of organoids had distinct differences in their fluid-secreting capacities, with nasal organoids having larger lumens (fluid-filled cavities) capable of greater fluid secretion. Similar differences were observed in organoids formed from CF cells or cells taken from healthy people.

Indeed, when compared with bronchial organoids, nasal organoids derived from CF patients exhibited greater swelling in response to a substance that induces fluid secretion.

Bronchial organoids, but not nasal ones from CF patients, were responsive to the components of Orkambi (lumacaftor and ivacaftor). That likely indicates fluid secretion in the nasal epithelium is CFTR-independent, the researchers noted.

The nasal cells also were found to have higher expression of a range of genes potentially involved in fluid absorption and secretion.

“These findings demonstrate the complex and multifaceted nature of the differences in nasal and bronchial fluid secretion and absorption,” the researchers wrote. Altogether, the data indicated that the distinct genetic and cellular profiles of the two cell layers likely underlie these differences.

More research needed

Still, “more research is needed to gain insight into the mechanisms underlying the differential CFTR-independent fluid secretion between nasal and bronchial organoids,” the scientists added.

More broadly, the researchers believe the findings demonstrate that cultured nasal and bronchial epithelial cells in the lab can serve as “excellent models to further explore the contribution of tissue-specific characteristics on upper and lower respiratory disease development in CF.”