The growing worldwide epidemic of respiratory diseases can be attributed to simple everyday factors such as tobacco smoke, air pollution, occupational chemicals, or dust.

These diseases involve the infection or irritation of the airways which can cause serious conditions such as chronic obstructive pulmonary disease, asthma, or lung cancer. Chronic respiratory disease is incredibly widespread yet it is still not curable with limited treatment options involving the alleviation of symptoms through the dilatation of major air passages.

How our airways protect us

In practical terms, the body’s airways are a conduit for the air in our environment to enter the lungs, achieved through the inhalation of oxygen via the nose and mouth. It is in this way the airways also act as the body’s first line of defense against airborne infectious particles.

Specifically, two types of airway cells play a vital role in this process: mucus cells, which secrete mucus to trap harmful particles, and ciliated cells, which use their finger-like projections to move the mucus-engulfed particles out of the lungs to the back of the throat.

If these antigens are not successfully cleared from the respiratory system they can injure the airways which, in turn, activates airway basal stem cells to repair the damage by proliferating or differentiating into mucus and ciliated cells. However, the signaling pathways and mechanisms mitigating the activation of these stem cells are still largely unknown.

Now, a study from researchers at UCLA identifies the pathways airway basal stem cells in the lungs need to switch between two distinct phases whilst regenerating lung tissue after an injury. The team states their results shed light on how aging can cause lung regeneration to go awry, possibly leading to lung cancer and other respiratory-based diseases. The study is published in the journal Cell Stem Cell.

Previous studies have indicated airway basal stem cells are charged with maintaining the equilibrium between the amount of mucus and ciliated cells produced to keep harmful particles out of the lungs. This already precipitous role is further complicated by the fact they must self-renew to ensure there will be enough basal stem cells to respond to the next injury.

This has led to confusion regarding dynamic interactions between airway basal stem cells and their signaling niches, the supportive environment that surrounds them, to respond to an insult or aging. Therefore, understanding how regeneration occurs in healthy lungs is a crucial step to understanding how certain diseases can arise when the process goes astray.

Recent studies from the group established a link between lung cancer and the Wnt/beta-catenin pathway, a signaling pathway that regulates many cellular functions including proliferation, differentiation, and stem cell renewal.

Whilst observing this cellular signaling pathway in action they noted the more a cell divides, the more likely it is a mutation can occur to cause cancer, leading them to focus on this molecule. The current study investigates the role of the Wnt pathway in regulating airway basal stem cells in the respiratory system.

How we respond to lung injuries

The current study analyzes how the different types of cells found in the airway basal stem cell niche orchestrate the repair response in transgenic mice with lung injuries. The research demonstrated the Wnt/beta-catenin signaling pathway stimulates the airway basal stem cells to respond to injury. The Wnt pathway does so by originating in one cell type to initiate proliferation and another cell type to initiate differentiation.

Results show in the proliferation phase of repair, a connective tissue cell called a fibroblast secretes the Wnt molecule, which then signals to the stem cells that it’s time to self-renew. Data findings show in the differentiation phase of repair, the Wnt molecule is secreted by epithelial cells lining the respiratory system to signal to the stem cells to produce mature airway cells.

The lab honed in on the aforementioned activity of this regenerative process in the lungs of older mice to identify the part it may play in age-related disease. Findings suggest the elderly Wnt pathway is constantly stimulating the stem cells even when there is no injury, in contrast to the young respiratory systems where it is only activated when necessary.

The group goes on to expand when this pathway is active, it stimulates the stem cells to produce more cells, even if they’re not needed in the older animals, raising the risk for mutations.

Implications of this study

The team surmises they have identified which distinct phases of respiratory immunity, aging, and regeneration the Wnt pathway regulates. For the future, the researchers state they have provided insight into which cell types and pathways are implicated in the formation of lung cancer, with the view to developing preventative therapies.

Source: UCLA Health

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