Researchers here report on potential targets to enhance the regenerative capacity of alveolar type 2 cells, a population necessary for regeneration in lung tissue, but which falters in this duty in the context of progressive and age-related lung disease. Compensating for poorly understood mechanisms of damage and disease that direct alveolar type 2 cells away from regenerative activity can in principle be achieved by overriding the regulatory system that controls this aspect of cell behavior, provided enough is understood of how that regulatory system works. This approach to therapy doesn't fix the underlying issues, but may well prove to be beneficial enough to pursue. There are numerous examples in the present practice of medicine of compensatory approaches that succeed in producing benefits for patients.
When a person's lungs are damaged, that organ's survival depends on a small but powerful set of cells that must choose whether to repair the tissue or fight infection. "We were surprised to find that these specialized cells cannot do both jobs at once. 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."
The new research centers on alveolar type 2 (AT2) cells, which play a dual role in the lung. These cube-shaped cells secrete surfactant proteins that keep air sacs open, but they also act as reserve stem cells capable of regenerating alveolar type 1 (AT1) cells - the paper-thin cells that form the surface for gas exchange. This regenerative capacity makes AT2 cells essential for lung repair after injury. 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 discoveries could guide the development of therapies to fix AT2 cells that are broken in disease. Drugs that target C/EBPα, for example, may restore repair programs or reduce scarring in pulmonary fibrosis.
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