New discovery may unlock regenerative therapies for lung disease

ROCHESTER, Minnesota — Mayo Clinic researchers have identified a molecular "switch" in lung cells that helps them decide when to repair tissue and when to fight infection. This discovery could guide future regenerative therapies for chronic lung diseases. 

"We were surprised to find that these specialized cells cannot do both jobs at once," says Douglas Brownfield, Ph.D., senior author of the study, which was published in Nature Communications. "Some commit to rebuilding, while others focus on defense. That division of labor is essential. And by uncovering the switch that controls it, we can start thinking about how to restore balance when it breaks down in disease." 

How lung cells balance repair and defense 

The new research centers on alveolar type 2 (AT2) cells, specialized cells that both protect the lungs and serve as backup stem cells. These cells produce proteins that keep air sacs open for breathing, but they can also regenerate the thin alveolar type 1 (AT1) cells that form the surface for oxygen exchange.  

For decades, scientists have known that these cells often fail to regenerate properly in lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) and severe viral infections like COVID-19. What remained unclear was how AT2 cells lose their stem cell capacity. 

Using single-cell sequencing, imaging and preclinical injury models, the team mapped the developmental "life history" of AT2 cells. They found that newly formed AT2 cells stay flexible for about one to two weeks after birth before "locking in" to their specialized identity.  

That timing is controlled by a molecular circuit involving three key regulators called PRC2, C/EBPα, and DLK1. The researchers showed that one of them, C/EBPα, acts like a clamp that suppresses stem cell activity. In adult lungs, AT2 cells must release this clamp after injury to regenerate.  

The same molecular switch also directs whether AT2 cells repair lung tissue or defend against infection. That helps explain why infections often slow recovery from lung disease. 

"When we think about lung repair, it's not just about turning things on — it's about removing the clamps that normally keep these cells from acting like stem cells," says Dr. Brownfield. "We discovered one of those clamps and how it times the ability of these cells to repair." 

Preventing organ failure 

The discoveries highlight potential new targets for regenerative medicine. Drugs designed to adjust the C/EBPα, for example, could help AT2 cells rebuild lung tissue more effectively or reduce scarring in pulmonary fibrosis.  

"This research brings us closer to being able to boost the lung's natural repair mechanisms, offering hope for preventing or reversing conditions where currently we can only slow progression," says Dr. Brownfield.  

The findings also may guide earlier detection, helping clinicians identify when AT2 cells are stuck in one state and unable to regenerate. Such insights could lead to new biomarkers for lung disease. This work aligns with Mayo Clinic's Precure initiative, which focuses on detecting disease at its earliest stages — when interventions are most effective — and preventing progression before organ failure occurs.  

At the same time, the research advances Mayo Clinic's Genesis initiative, which aims to prevent organ failure and restore function through regenerative medicine. The team is now testing strategies to remove the repressive clamp on human AT2 cells, expand them in culture and potentially use them for cell replacement therapy. 

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