Lung repair – how our bodies fix themselves (and sometimes don't)

 

Image credit: Science (2024). DOI: 10.1126/science.ado5561

Our lungs are amazing organs. They allow us to breathe, taking in the oxygen we need to live and getting rid of carbon dioxide. But like any part of the body, they can get damaged. Sometimes, this damage is minor, like a small cut, and our lungs can fix themselves. This is called "euplastic regeneration," where the lung cells get to work, replacing the damaged tissue and getting everything back to normal. However, when the damage is severe, things can go a bit wrong, and the repair process becomes "dysplastic".

Think of it like this: euplastic repair is like a perfect patch on your favorite jumper, and dysplastic repair is like an uncoordinated repair with lots of extra threads hanging off. In the case of the lung, this dysplastic repair can mean that the lung doesn't work as well as it should.

So, what makes the difference? Well, it turns out that different types of cells in the lungs play a crucial role. There are two main types of cells that are involved in lung repair:

• Alveolar cells (AT2): These are the main "stem cells" in the lung, and when the damage is mild to moderate, these cells regenerate the alveoli (the tiny air sacs responsible for gas exchange).

• Basal cells (Krt5+): These cells usually live in the airways, but after severe damage, they can migrate into the damaged areas of the lung and start growing and causing problems. These cells are marked by a protein called Krt5.

When there is severe damage, the basal cells move in and take over, creating a new, injury-induced niche. This is where different kinds of fibroblasts come in.

Fibroblasts: The helpers (and sometimes hinders)
Fibroblasts are cells that are crucial for the structure of our lungs. There are two main types:

• AF1 cells (Pdgfra+): These are the reactive mesenchymal cells that respond to injury. They are marked by a protein called Pdgfra. After injury, they proliferate and can turn into other types of cells.

• AF2 cells (Pdgfrb+): These are another type of fibroblast, marked by the protein Pdgfrb. They don’t proliferate or change their type, but they play an important role in the repair process.

After injury, AF1 cells can transform themselves into myofibroblasts, and then eventually differentiate into AF2 cells. These AF1-derived AF2 cells end up in the injury-induced niche, right next to the problematic Krt5+ basal cells. It turns out that these AF1-derived AF2 cells and the Krt5+ basal cells talk to each other through something called Notch signaling. It's like they're sending messages back and forth.

Notch signaling: The bad messenger
Notch signaling involves proteins on the surface of cells which, when activated, send messages inside the cells. In the lung, it turns out that this Notch signaling between the AF1-derived AF2 cells and the Krt5+ basal cells, promotes the dysplastic repair process.

The AF1 cells rely on Notch signaling to establish the injury-induced niche, which actually encourages the Krt5+ basal cells to take over. This is bad news because the expansion of Krt5+ cells actually blocks the normal, helpful repair process of the alveolar cells (AT2) and prevents the lung from restoring normal gas exchange.

However, when the researchers blocked Notch signaling in the AF1 cells, they found something amazing! The balance shifted, and instead of dysplastic repair, they saw an increase in signals that promote euplastic repair. Specifically, blocking Notch signaling increased the levels of Wnt and Fgf signaling, which are good for alveolar cell regeneration.

What does this mean?
This research has identified a critical role for the AF1 cells in directing lung repair. The signals these cells send are crucial in deciding whether the lung undergoes proper regeneration (euplastic) or a poor repair (dysplastic) after serious injury. The study suggests that by targeting these AF1 cells and their Notch signaling, it might be possible to promote better lung repair.

The researchers have also found that in human lung diseases, similar signaling patterns are seen in fibrotic lung diseases (like post-COVID-19 fibrosis). In these cases, there is the same problematic Notch signaling, which means the dysplastic response continues. But in degenerative lung diseases such as COPD and AAT deficiency, a different, regenerative signaling pattern can be seen.

Looking ahead
This new research highlights how complex the lung repair process is and also identifies some key cell types and signaling pathways that could be targeted by future therapies to improve recovery after lung injury and disease. It is an important step towards understanding and treating conditions like lung fibrosis, where the repair process has gone awry.

Journal information: An injury-induced mesenchymal-epithelial cell niche coordinates regenerative responses in the lung. Science (2024). DOI: 10.1126/science.ado5561

Additional information: https://www.science.org/journal/science