New Cell Type Identified With Major Role In Cystic Fibrosis

Over 70,000 people around the world are living with cystic fibrosis—a genetic disease that causes a thick buildup of mucus in the lungs, leading to persistent infections and difficulty breathing.

A new study in Nature from NYSCF – Robertson Stem Cell Investigator Jay Rajagopal, MD (a physician in Pulmonary and Critical Care at Massachusetts General Hospital, associate member at the Broad Institute of MIT and Harvard, and professor at Harvard Medical School) identifies a previously uncharacterized cell type that plays an important role in cystic fibrosis onset. Dr. Rajagopal’s team also examined gene expression in the different cell subtypes of the airway, finding new genes that could lead to a variety of airway diseases such as asthma, chronic obstructive pulmonary disease, and bronchitis.

“We have the framework now for a new cellular narrative of lung disease,” said Dr. Rajagopal in a press release issued by the Broad Institute today. “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.”

The team used a technique called single-cell RNA sequencing (followed by a new method called pulse-seq) to analyze thousands of cells in the airways of mice, looking at what genes were expressed across time and where different cell subtypes were located. The results were then validated in human tissue generated from stem cells.

With a more detailed “map” of the airway, the team could then start to pinpoint important abnormalities. Specifically, the researchers noticed that one cell subtype expressed levels of the CFTR gene (the gene that causes cystic fibrosis) at a much higher rate than any other cell type. This cell subtype was previously uncharacterized, as it constitutes under 1% of cells in the airway. Because it carries a similar function to ionocytes (cells found in fish gills and frog skin), the team dubbed these new cells “pulmonary ionocytes.”

Previously, researchers thought that cystic fibrosis was caused by low levels of CFTR expression in a large number of cells called ciliated cells. However, the new data suggests that CFTR expression occurs in just a few of these pulmonary ionocytes, and that this is enough to drive the disease. Equipped with this information and a roadmap of the cells in the airway, scientists can now develop cystic fibrosis treatments that target the right cells.

“The atlas that we’ve created is already starting to drastically re-shape our understanding of airway and lung biology,” said Dr. Aviv Regev, a co-author of the study, director of the Klarman Cell Observatory at the Broad Institute, and professor of biology at MIT. “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.”

Montoro DT, Haber AL, Biton M et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. Online August 1, 2018. DOI: 10.1038/s41586-018-0393-7