NEW YORK – Transcriptome profiles from individual airway cells are providing a new look at cystic fibrosis (CF) biology and the cellular subpopulations that are altered in individuals with end-stage forms of the disease.
"Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease," the authors explained in a paper published in Nature Medicine on Thursday.
Researchers at the University of California, Los Angeles; Cedar-Sinai Medical Center; the Cystic Fibrosis Foundation's CFFT Lab; and elsewhere performed single-cell RNA sequencing on proximal airway epithelium samples from 19 individuals being treated for end-stage lung disease, along with samples from disease-free lung donors. They compared expression-based cell clusters in samples with or without CF, using molecular signatures in individual cells to identify subsets of ciliated, secretory, and basal cell types in the lung tissue.
"Prior studies have examined the human airway in terms of the major cell populations but our work using a single-cell approach has allowed us to identify subpopulations of cells within these major cell subtypes, and this shows us how dynamic and complex the airway cells are," co-senior and co-corresponding author Brigitte Gomperts, a physician-scientist at the UCLA Broad Stem Cell Research Center and a professor of pediatrics and pulmonary medicine at the David Geffen School of Medicine at UCLA, said in an email. She noted that cell subtype differences detected in CF samples make it possible to better understand the autosomal recessive condition.
The team's findings pointed to higher-than-usual levels of basal cells that appeared to be undergoing a transition to become specialized ciliated cells or specific secretory cell subtypes in the CF samples, along with subpopulations of secretory cells linked to enhanced mucus secretion and immune activity against pathogenic microbes. On the other hand, the representation of cycling basal cells — stem cells contributing to upper airway repair and tissue regeneration — appeared to drop off in the CF-affected samples.
"We suspect that changes the basal cells undergo to replenish ciliated cells represent an unsuccessful attempt to clear mucus that typically accumulates in airways of patients with cystic fibrosis," co-senior and co-corresponding author Barry Stripp, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute's lung stem cell program, said in a statement.
Based on these and other results, the investigators speculated that the CF-associated reduction in stem cell subpopulations may reflect exhaustion of these cell types that is related to the need for ongoing tissue repair related to CF-related injury to the airway. Gomperts explained that long-lived stem cell subpopulations might serve as a therapeutic target in the future.
More broadly, the investigators suggested that the results from the single-cell transcriptome analysis may offer previously unappreciated insights into CF. Though the disease has most pronounced effects on the lungs, they noted that it can also contribute to problems in other organs, since CFTR mutations lead to electrolyte transport changes in polarized epithelial cells.
"The molecular profiles of basal cell subsets described herein will guide strategies aimed at targeting gene-corrective cargo to long-lived basal stem cells of the CF airway," they wrote, adding that "a molecular roadmap of the normal and CF airway provides a framework to assess therapeutic interventions aimed at correction of both electrolyte transport defects and broader changes in epithelial cell composition and function in airways of patients with CF."