Two independent teams of scientists have identified a rare cell type in airway tissue — previously uncharacterized in the literature — that appears to play a key role in the biology of cystic fibrosis, a multiorgan disease that affects more than 70,000 people worldwide. Named pulmonary ionocytes, these cells appear to be the primary source of activity of a gene called cystic fibrosis transmembrane conductance regulator (CFTR), mutations to which cause cystic fibrosis.
Pulmonary ionocytes (orange) extend through neighboring epithelial cells in the upper respiratory tract of the mouse, to the surface of the epithelial lining; cell nuclei in cyan. Image credit: Montoro et al, doi: 10.1038/s41586-018-0393-7.
Despite decades of research on the CFTR gene and progress in treating the disease, there is still no cure.
The new findings, reported in two papers in the journal Nature, show that CFTR activity is concentrated in a small, previously unknown population of cells.
“As researchers work toward cures for cystic fibrosis, knowing you are looking at 1% of the cell population seems essential for any type of trouble shooting to improve a therapy or develop new therapies,” said Harvard Medical School’s Dr. Allon Klein, co-lead author of one of the papers.
The studies also revealed the characteristics of other new, rare and poorly understood cell types, which expands the current understanding of lung biology and disease.
“Cystic fibrosis is an amazingly well-studied disease, and we’re still discovering completely new biology that may alter the way we approach it,” said Harvard Medical School’s Professor Jayaraj Rajagopal, co-corresponding author of the second paper.
“We have the framework now for a new cellular narrative of lung disease.”
Using single-cell sequencing technology, both teams analyzed gene expression in tens of thousands of individual cells isolated from human and mouse airways.
Comparing patterns of gene expression and using previously described cells as references, the researchers created comprehensive catalogues of different cell types and states, as well as their abundance and distribution.
Their analyses mapped out the genetic identities of both known and previously undescribed cell types.
One new cell type, pulmonary ionocytes, was particularly striking as they expressed higher levels of CFTR than any other cell.
“These cells appear to play a role in this process, which is necessary for clearing mucus from the airways,” the scientists said.
Identified in the 1980s, CFTR codes for a protein that transports chloride ions across cell membranes.
Mutations to this gene can lead to the buildup of thick mucus in the lung, pancreas and other organs, which in turn leads to frequent respiratory infections and other symptoms that characterize cystic fibrosis.
Researchers have long assumed that CFTR is expressed at low levels in ciliated cells, a common airway cell type.
The new studies, however, suggest that the majority of CFTR expression occurs in pulmonary ionocytes, which make up only around 1% of airway cells.
They showed that the activity of CFTR, not just its expression, relates to the number of pulmonary ionocytes in the tissue.
“With single-cell sequencing technology, and dedicated efforts to map cell types in different tissues, we’re making new discoveries — new cells that we didn’t know existed, cell subtypes that are rare or haven’t been noticed before, even in systems that have been studied for decades,” Broad Institute of MIT and Harvard member and MIT Professor Aviv Regev, co-lead author of the second paper.
Professor Regev and co-authors disrupted a critical molecular process in pulmonary ionocytes in mice, they observed the onset of key features associated with cystic fibrosis, notably the formation of dense mucus.
“This finding underscores how important these cells are to airway-surface regulation,” the scientists said.
“Together, the teams’ discoveries point to new strategies for treating cystic fibrosis, such as increasing the amount of pulmonary ionocytes to increase the amount of CFTR activity,” said Novartis Institutes for BioMedical Research’s Dr. Aron Jaffe, co-lead author of the first study.
“The identification of these cells can also help guide teams trying to use gene therapy to correct CFTR mutations.”
“We can use this information to be a bit more clever when we devise therapeutic approaches to cystic fibrosis.”
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Lindsey W. Plasschaert et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature, published online August 1, 2018; doi: 10.1038/s41586-018-0394-6
Daniel T. Montoro et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature, published online August 1, 2018; doi: 10.1038/s41586-018-0393-7
