New, Rare Cell Type in Lung Airways Identified as Key Carrier of CFTR Gene, Study Reports

A previously undiscovered and rare type of cell has been identified in the tissue lining the airway of the lungs and carrying high levels of the CFTR gene, the mutation of which is the underlying cause of cystic fibrosis (CF), a study reports.

While the exact role of these cells, named “ionocytes” by the researchers, in CF is still unknown, the findings from this study highlight their potential as targets for future therapeutics.

The study, “A revised airway epithelial hierarchy includes CFTR-expressing ionocytes,” was published in the journal Nature.

Lung airways are composed of different cell types, but scientists don’t know yet how the diversity of cell types is linked with diseases such as CF.

Three types of cells — basal cells, club cells, and ciliated cells — are present in higher numbers in the airways of the lungs, while another three types are much rarer –  tuft, neuroendocrine, and goblet cells.

Basal and club cells act as progenitor cells, meaning they can give rise to other cell types. Tuft cells have sensory functions, while goblet cells are the main producers of mucus in the lungs. Ciliated (brush-like) cells, together with mucus, make sure invaders of the airways are pushed out.

Researchers at the Broad Institute and Harvard and Massachusetts General Hospital (MGH) tackled this cell diversity in the airways using a technique called RNA sequencing applied to single, individualized airway cells.

RNA sequencing identifies all the RNA molecules inside cells, including the so-called messenger RNAs, which carry the genetic information encoded in genes.

The team analyzed the RNA profile of tens of thousands of cells from the airway of mice. They also developed a new method, called pulse-seq, to trace the mature cells back to their cell of origin, i.e., progenitor cells.

Their findings were then validated in human samples.

This led them to the discovery of an extremely rare cell type — composing just 1 percent of all total cells — that they called “pulmonary ionocytes.”

They coined the term “ionocytes” due to the cells’ similarity to ionocytes in the gills of fish and frog skin where they’re responsible for regulating the transport of ions and hydration.

The RNA profile of the pulmonary ionocytes was markedly different from that of the other cells. One of these striking differences was the levels of CFTR gene, which were much higher than in any other cell type.

For decades, researchers thought the CFTR gene was more prominent in ciliated cells, but these new results showed that expression of the CFTR gene is localized in a cell type they didn’t even know existed — ionocytes were the source of 54.4% of the CFTR gene’s activity, compared with 1.5% for ciliated cells.

“Cystic fibrosis is an amazingly well-studied disease, and we’re still discovering completely new biology that may alter the way we approach it,” Jayaraj Rajagopal, MD, co-lead author of the study, said in a press release. “At first, we couldn’t believe that the majority of CFTR expression was located in these rare cells, but the graduate students and postdocs on this project really brought us along with their data.”

Deleting an important gene, called Foxi1, in mouse ionocytes caused an accumulation of mucus in the animals’ airways, a phenomenon also seen in animal models of CF.

While the role of the CFTR-rich ionocytes in maintaining the airway’s function and in diseases like CF still needs to be clarified, these results may help researchers design new CF therapies — for example, by using gene therapies that deliver a corrected version of the CFTR gene to the right cells.

Researchers also identified which cells in the airway epithelium express genes linked to asthma.

They found that the tuft, neuroendocrine, and ionocyte cells arise directly from a common progenitor, basal cells. They also identified a new structure, which researchers called “hillocks,” in the lung airways characterized by rapid proliferating cells. The function of these structures in the lung remains unknown.

Overall, these new findings are “already starting to drastically re-shape our understanding of airway and lung biology,” said Aviv Regev, PhD, director of the Klarman Cell Observatory and co-lead author of the study. “And, for this and other organ systems being studied at the single-cell level, we’ll have to drape everything we know on top of this new cellular diversity to understand human health and disease.”

“We’ve uncovered a whole distribution of cell types that seem to be functionally relevant. What’s more, genes associated with complex lung diseases can now be linked to specific cells that we’ve characterized. The data are starting to change the way we think about lung diseases like cystic fibrosis and asthma,” said Rajagopal, who is a physician in the Pulmonary and Critical Care Unit at MGH, associate member at the Broad Institute, and a Howard Hughes Medical Institute faculty scholar.

A team of researchers at Harvard Medical School and the Novartis Institutes for BioMedical Research, working independently, reached the same results. Their study, also published in Nature, is titled, “A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte.”