Researchers at the Perelman School of Medicine at the University of Pennsylvania have discovered a new cell type within the lungs that may play a role in human lung diseases and pave the way for treatments for chronic obstructive pulmonary disease (COPD).
The findings are published in the journal Nature in a paper titled, “Human distal airways contain a multipotent secretory cell that can regenerate alveoli.”
“The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease,” the researchers wrote. “In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mice, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways.”
The researchers analyzed human lung tissue to identify the new cells, which they call respiratory airway secretory cells (RASCs). They also demonstrated that RASCs have stem-cell-like properties enabling them to regenerate other cells that are essential for the normal functioning of alveoli. In addition, they uncovered evidence that cigarette smoking and COPD can disrupt the regenerative functions of RASCs—hinting that correcting this disruption could be a good way to treat COPD.
“COPD is a devastating and common disease, yet we really don’t understand the cellular biology of why or how some patients develop it. Identifying new cell types, in particular new progenitor cells, that are injured in COPD could really accelerate the development of new treatments,” said study first author Maria Basil, MD, PhD, an instructor of pulmonary medicine.
Edward Morrisey, PhD, the Robinette Foundation professor of medicine, a professor of cell and developmental biology, and director of the Penn-CHOP Lung Biology Institute at Penn Medicine, and his team uncovered evidence of RASCs while examining gene-activity signatures of lung cells sampled from healthy human donors. They soon recognized that RASCs, which don’t exist in mouse lungs, are “secretory” cells that reside near alveoli and produce proteins needed for the fluid lining of the airway.
“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 Morrisey, who is also senior author the study.
Observations of gene-activity similarities between RASCs and an important progenitor cell in alveoli called AT2 cells led the team to a further discovery: RASCs, in addition to their secretory function, serve as predecessors for AT2 cells—regenerating them to maintain the AT2 population and keep alveoli healthy.
AT2 cells are known to become abnormal in COPD and other lung diseases, and the researchers found evidence that defects in RASCs might be an upstream cause of those abnormalities. In lung tissue from people with COPD, as well as from people without COPD who have a history of smoking, they observed many AT2 cells that were altered in a way that hinted at a faulty RASC-to-AT2 transformation.
Further research is needed. However, the findings pave the way for the possibility of future COPD treatments that work by restoring the normal RASC-to-AT2 differentiation process—or even by replenishing the normal RASC population in damaged lungs.
“These data identify a distinct progenitor in a region of the human lung that is not found in mice that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease,” the researchers wrote.
