Researchers in the U.S. have identified a new cell type in the narrowest airways of the lungs that, besides being involved in producing the mucus lining the airways, can give rise to alveolar epithelial type 2 (AT2) cells, which are involved in lung tissue repair and regeneration.
This cell type, named respiratory airway secretory cells (RASCs), and AT2 cells showed similarly altered gene activity in people with chronic obstructive pulmonary disease (COPD), highlighting a dysfunctional RAS-to-AT2 cell maturation in the disease.
“COPD is a devastating and common disease, yet we really don’t understand the cellular biology of why or how some patients develop it,” Maria Basil, MD, PhD, the study’s first author and an instructor of pulmonary medicine at University of Pennsylvania’s Perelman School of Medicine, said in a press release.
“With studies like this we’re starting to get a sense, at the cell-biology level, of what is really happening in this very prevalent disease,” said Edward Morrisey, PhD, the study’s senior author.
Morrisey is the Robinette Foundation professor of medicine, a professor of cell and developmental biology, and the director of the Penn-CHOP Lung Biology Institute at Penn Medicine.
“Identifying new cell types, in particular new progenitor cells, that are injured in COPD could really accelerate the development of new treatments,” Basil said.
These findings were detailed in the study, “Human distal airways contain a multipotent secretory cell that can regenerate alveoli,” published in Nature.
COPD, associated mainly with long-term exposure to irritants such as cigarette smoke, is characterized by excessive airway inflammation, and abnormal repair and remodeling of the lung epithelium — the tissue that lines the airways. This often results in the progressive destruction of the alveoli, the tiny lung air sacs responsible for gas exchange in the lungs.
In human lungs, the main airways (bronchi) branch off into smaller and smaller airways, with the smallest, called terminal bronchioles, ending in alveoli. Between the terminal bronchioles and the alveoli there is a mixed structure called the respiratory bronchioles.
“Emerging evidence suggests that [respiratory bronchioles are] disrupted in several human lung diseases including COPD, viral infections and aging,” the researchers wrote.
However, given “the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized,” they said.
Morrisey and his team, along with colleagues at other U.S. institutions, discovered a unique cell type in respiratory bronchioles that may be involved in the cellular and molecular defects seen in COPD and other lung diseases.
By analyzing the gene activity of lung tissue from five healthy nonsmoker donors, researchers were able to distinguish several lung cell types, including two distinct populations of secretory cells, which are involved in producing the mucus that lines the airways.
One such cell population showed a new, distinct gene activity profile relative to the well-known lung secretory cells — present in larger airways — and was found mainly in patches within respiratory bronchioles while being scarce in terminal bronchioles.
These cells, called RASCs, had a molecular profile that stood between standard lung secretory cells and AT2 cells, and were able to mature into AT2 cells.
AT2 cells are a type of cell lining the alveoli and the respiratory bronchioles that’s involved in maintaining and regenerating the alveoli and is known to be affected in COPD.
The findings suggest that defects in RASCs may be responsible for COPD-related abnormalities in AT2 cells.
To confirm if this was the case, researchers analyzed lung tissue from COPD patients undergoing lung transplant and from people without the disease, but who were either active smokers or had recently quit smoking.
Results showed that RASCs and AT2 cells from COPD patients exhibited similar, abnormal molecular profiles relative to those from healthy people that were distinct from those of other lung cell types.
Both COPD and increasing exposure to cigarette smoke were associated with a significant increase in an abnormal subset of AT2 cells that showed markers of RASCs, suggesting a faulty RASC-to-AT2 cell maturation.
The accumulation of these abnormal AT2 cells “could represent either a more active transitioning or a stall during the transitioning of these cells,” the researchers wrote.
They also found that RASCs maturation into AT2 cells was regulated by two major cell-fate signaling pathways: the Notch and the Wnt pathways.
These findings highlight a “dysfunction of RAS cell to AT2 cell [maturation] in COPD, which is consistent with the known anatomical abnormalities that occur in the distal respiratory bronchioles and the alveolar niche in this disease,” the researchers wrote.
Also, “chronic smoke-induced injury is associated with aberrant RAS cell to AT2 cell maturation,” they added.
“These data characterize a poorly understood architectural niche in the human lungs that is populated by a distinct cell lineage that has the ability to generate AT2 cells and participate in alveolar regeneration,” the research team wrote.
“Given the critical role that the respiratory bronchioles have in both normal human lung [function] and chronic disease, future studies into this region should reveal additional insights into this distinct niche of the human lungs,” researchers said.
The results also suggest that restoring normal RASC-to-AT2 cell maturation, or even replenishing the normal RASC population, may be new therapeutic strategies to halt further damage in COPD.
The study was supported by the National Institutes of Health, the BREATH Consortium/Longfonds of the Netherlands, the Parker B. Francis Foundation, and GlaxoSmithKline.