A multi-institute consortium study reports single-cell transcriptomics data that compares cells lining the airways of cystic fibrosis (CF) patients undergoing transplantation for terminal lung disease with that of previously healthy lung donors in a first-of-its-kind molecular atlas.

This resource holds the potential to facilitate scientists’ search for rare stem cells that regenerate the airways over a person’s lifetime and can be targeted for genetic and cell therapies for CF that may provide long-term or permanent remedies.

Mutations in the gene CFTR (cystic fibrosis transmembrane conductance regulator) in CF patients cause progressive multi-organ dysfunction due to abnormal electrolyte transport across biological barriers but lung disease is by far the most predominant cause of affliction in CF patients. Mutant cells produce unusually thick and sticky mucus that clogs the airways and traps pathogens that can cause life-threatening infections and irreversible lung damage.

The team describes this gene expression catalog of epithelial cells in the deep airducts of the lung in a Nature Medicine article titled, “Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition.”

From left to right, Barry Stripp, PhD, Brigitte Gomperts, PhD, Kathrin Plath, PhD, and John Mahoney, PhD [Source: Reed Hutchinson/UCLA Broad Stem Cell Research Center]
Brigitte Gomperts, MD, physician-scientist at the UCLA Broad Stem Cell Research Center, professor of pediatrics and pulmonary medicine at the David Geffen School of Medicine at UCLA and co-first author on the study said, “This transcriptomic catalog is allowing us to better understand the stem cell subpopulations in the airways of patients with healthy lungs and those with cystic fibrosis. Ultimately, we would like to target the long-lived stem cells with gene therapy for cystic fibrosis. This is the first step to better understanding which stem cell subpopulation(s) we should target in the future.”

“This research provides critical insight into how the disease alters the cellular makeup of the airways, which will enable scientists to better target the next generation of transformative therapies for all people with cystic fibrosis,” said John Mahoney, PhD, head of the stem cell biology team at the Cystic Fibrosis Foundation Therapeutics Lab and a senior author on the paper.

“[This atlas] can serve as an essential tool in the continued quest to develop new therapies aimed at targeting the underlying cause of CF disease. Due to the complex and dynamic nature of CF disease, combining transcriptomic analysis of gene expression gleaned from the atlas with an experimental scientific discipline such as physiology, can lead to advanced understanding of the pathogenesis of CF disease,” said My N. Helms, PhD, associate professor in the pulmonary division, department of internal medicine at the University of Utah and chair of the Cell and Molecular Physiology Section of the American Physiological Society, as an expert unrelated to the study.

The lining of the airducts in our lungs is a composite of several cell types and includes various types of secretory cells, ciliated cells, and cycling basal cells. The authors showed an increase of specialized ciliated and secretory cell types coupled with a decrease in cycling basal epithelial cells in CF airways.

“We were surprised to find that the airways of people with cystic fibrosis showed differences in the types and proportions of basal cells, a cell category that includes stem cells responsible for repairing and regenerating upper airway tissue, compared with airways of people without this disease,” said Barry Stripp, PhD, professor of medicine, director of the lung stem cell program at the Cedars-Sinai Board of Governors Regenerative Medicine Institute and a senior author on the study. “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.”

As part of the study, the researchers compared lung tissue samples from 19 patients with CF with samples from healthy lungs donated by individuals who showed no chronic lung disease. Scientists at the three collaborating institutions used distinct but similar methods to break down the tissue samples. Single-cell RNA sequencing and novel bioinformatic tools allowed them to analyze thousands of cells in tandem and classify them into subtypes, including some previously unknown subtypes, based on their gene expression patterns.

“The next major step is functional validation of each of these stem cell subpopulations in appropriate airway models to be able to understand what their regenerative capacity is,” said Gomperts. In future studies, the team also intends to investigate the causes underlying aberrant basal cell cycling and identify long-lived basal stem cells that would be the ideal target for a CFTR gene correction.

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