Mouse lung stem cells switch identities to help repair damaged airways

by Sanjukta Mondal, Medical Xpress

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edited by Sadie Harley, reviewed by Robert Egan

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The lung is divided into two main anatomical parts: the airways, called bronchioles, which carry air in and out, and the alveoli, the tiny air sacs where oxygen exchange occurs. When injury or damage occurs in either region, that region deploys its own team of specialized cells, like stem cells, to keep things working. While scientists have known that airway stem cells move into the alveoli to help repair gas-exchange tissue, can the stem cells also make the reverse journey?

In a recent study published in Nature, a team of researchers in China used a specialized technique called dual-recombinase genetic cell-tracking systems in mice to investigate whether stem cells in the alveoli could reverse course and cross anatomical boundaries to repair damaged airways.

In injured mouse lungs, some alveolar type 2 (AT2) stem cells left the air sacs, crossed into the small airways and transformed into mature airway-lining cells, mainly club cells and ciliated cells, to replace damaged tissue.

Over time, these converted cells matured functionally to match native airway cells. In one chemical-injury experiment, AT2 cells produced about 52% of the regenerated club cells after four weeks. Immune cells also released a protein called SPP1, which lured AT2 cells toward the damaged airways through a receptor called integrin β1.

Tracking the transformation

When diseases such as asthma, pneumonia and bronchiectasis damage the bronchial lining, the lungs can struggle to rebuild it. Efforts to repair this damage have largely centered on stem cells already living in the lungs. Every compartment in the lungs has its own specialized cells to keep the tissue healthy.

In the trachea, basal cells serve as stem cells, developing into different cell types to maintain the lining. In the bronchioles, club cells and neuroendocrine (NE) cells step in to repair local damage. In the alveoli, AT2 cells renew themselves and develop into alveolar type 1 (AT1) cells, which let the lungs exchange oxygen and carbon dioxide.

The journey of club cells and neuroendocrine (NE) cells to the alveoli has been documented in previous studies, but not much was known about the role of AT2 cells in helping regenerate the bronchiolar lining.

To track how the lung responds to severe damage, researchers used two complementary approaches in mouse models: chemical injury that selectively destroys club cells in the bronchial airways and genetically engineered mice with cells expressing diphtheria toxin receptors in specific airway cells.

Researchers built genetic labels that distinguished AT2 cells from their neighboring stem cells in mice, then tracked their descendants after two types of airway injury. Using microscopy and single-cell molecular analyses, they tracked how the cells moved and changed identity along the way.

Traveling mechanics

They discovered that AT2 stem cells travel into damaged airways to help rebuild the lining. When an airway is injured, infiltrating immune cells release a signaling protein called SPP1. Nearby AT2 cells detect it through their surface receptor and crawl toward the wound. On arrival, they pass through a brief intermediate stage marked by CLDN4.

Once AT2 cells reach the injured airways, neighboring ciliated cells send them Notch signals, using ligands such as JAG1 to trigger their transformation into mature club cells. Each step in this process matters because any disruption in SPP1, ITGB1, CLDN4 or Notch signaling can hinder cells' migration process, delaying lung repair.

Current clinical strategies for airway disease focus mainly on the stem cells that already live in the airways. The findings demonstrate that the AT2 cells that call tiny air sacs their home can do more than maintain the alveoli, expanding our understanding of their plasticity and opening up new possibilities for regenerative medicine.

Written for you by our author Sanjukta Mondal, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Kuo Liu et al., Alveolar stem cells transdifferentiate to drive bronchiolar regeneration, Nature (2026). DOI: 10.1038/s41586-026-11127-w

Journal information: Nature

Clinical categories

Pulmonary medicine Who's behind this story?

Sanjukta Mondal

Master's in Chemistry. Freelance science journalist and communicator. Published in Chemistry World, BioSpace, and The Hindu. Full profile →

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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