New Lung Cell Type Linked to Cystic Fibrosis Emerges From Mouse, Human Cell Atlas Studies
NEW YORK (GenomeWeb) – Two new studies that used single-cell RNA sequencing to profile tracheal or bronchial tissue from mice or humans have provided a clearer understanding of the relationships between cells in the airway and lungs, while identifying a new cell type that appears to be relevant to cystic fibrosis biology.
"The atlas that we've created is already starting to drastically reshape our understanding of airway and lung biology," Aviv Regev, director of the Broad Institute's Klarman Cell Observatory and co-chair of the Human Cell Atlas consortium, said in a statement.
For one of the new studies, appearing online today in Nature, Regev, co-senior author Jayaraj Rajagopal, and colleagues from Massachusetts General Hospital, the Broad Institute, and elsewhere sequenced the RNA of almost 7,500 individual mouse tracheal epithelial cells and performed in vivo cell lineage tracing experiments, pulse-seq profiling, and lineage hierarchy analyses.
With this information, the team explored the origins, developmental trajectories, and interactions between cell types in the mouse airway, while identifying and characterizing previously unappreciated lung cell types and subtypes.
"We've uncovered a whole distribution of cell types that seem to be functionally relevant," Rajagopal, a regenerative medicine researcher affiliated with MGH, the Harvard Stem Cell Institute, and the Broad Institute, said in a statement.
"[G]enes associated with complex lung diseases can now be linked to specific cells that we've characterized," he added, noting that "data are starting to change the way we think about lung diseases like cystic fibrosis and asthma."
In particular, the team described a rare new cell type referred to as Foxi1+ pulmonary ionocytes, in a nod to the cells' gene expression ties to specialized ion transport-regulating ionocyte cells in fish and frogs. Those cells were marked by enhanced expression of the cystic fibrosis gene CFTR, which dropped off in mouse ionocytes missing the Foxi1 transcription factor-coding gene.
For a related study published online today in Nature, a Novartis Institutes for BioMedical Research-led team provided additional details on the pulmonary ionocyte cell type, based on its own analysis of single-cell RNA-seq data for more than 7,600 mouse tracheal epithelial cells and 2,970 primary human bronchial epithelial cells.
By incorporating electrophysiological, imaging, and other data, the researchers not only detected expression of Foxi1, CFTR, and vacuolar-type H+-ATPase subunits in the pulmonary ionocyte cells but also identified a crucial role for Notch signaling in the cell type.
More broadly, data collected across the mouse and human cell sets "reveals cell states that represent known and novel cell populations, delineates their heterogeneity, and identifies distinct differentiation trajectories during homeostasis and tissue repair," senior authors Aron Jaffe, a respiratory diseases researcher at the Novartis Institutes for BioMedical Research, and Allon Klein, a Harvard Medical School systems biology researcher, and their co-authors wrote.