A FIRST-OF-ITS-KIND MOLECULAR CATALOG OF CELLS in healthy lungs and the lungs of patients with cystic fibrosis (CF) reveals new subtypes of cells and illustrates how the disease changes the cellular makeup of the airways. The findings could help scientists in their search for specific cell types that represent prime targets for genetic and cell therapies for CF.
The catalog, developed by a team of researchers from UCLA, Cedars-Sinai and the Cyst ic Fibrosis Foundation, provides “valuable insights into the cellular makeup of both healthy and diseased airways,” says Dr. Brigitte N. Gomperts, MD, professor of pediatrics and of pulmonary medicine and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “If you can understand how things work in a state of health, it becomes easier to see what cellular and molecular changes occur in a disease state.”
A progressive genetic disorder that affects more than 70,000 people worldwide, CF results from mutations to the CFTR gene. Cells that contain the defective protein encoded by the gene produce unusually thick and sticky mucus that builds up in the lungs and other organs. This mucus clogs the airways, trapping germs and bacteria that can cause life-threatening infections and irreversible lung damage.
For the study, Dr. Gomperts and her research colleagues, who included Kathrin Plath, PhD, UCLA professor of biological chemistry and a member of the UCLA Broad Stem Cell Research Center, compared tissue samples taken from lungs removed from 19 transplant recipients with CF with samples taken from healthy lungs donated by 19 individuals who had died from other causes. Researchers at the three inst itutions employed similar but distinct methods to break these tissues down and examine them using a technology called single-cell RNA sequencing, which al lowed them to analyze thousands of cells simultaneously and classify them into subtypes based on their patterns of gene expression — that is, which genes are turned on and off.
“The process is analogous to taking a smoothie and ‘un-blending’ it to discover all the ingredients it contains, and then measuring how much of each ingredient was used,” Dr. Plath says. Using a novel computer- based bioinformatics approach to compare the gene expression patterns of the various cells, the team was able to create a catalog of the cell types and subtypes present in healthy airways and those affected by cystic fibrosis, including some previously unknown subtypes that illuminate how the disease alters the cellular landscape of the airways.
“We have made t remendous progress in the development of treatments for the underlying cause of cystic fibrosis, but many people cannot benefit from these medicines,” says John (Jed) Mahoney, PhD, head of the stem cell biology team at the Cystic Fibrosis Foundation Therapeutics Lab. “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.”
“Transcriptional Analysis of Cystic Fibrosis Airways at Single-cell Resolution Reveals Altered Epithelial Cell States and Composition,” Nature Medicine, May 6, 2021