Alveolar stem cells transdifferentiate to drive bronchiolar regeneration
6 affiliations
- 1Zhejiang Key Laboratory of Signaling Mechanisms in Tumor Progression and Intervention, School of Life Science, Hangzhou Institute for Advanced Study, Hangzhou, University of Chinese Academy of Sciences, Hangzhou, China
- 2CAS CEMCS-CUHK Joint Laboratory, New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- 3School of Life Science and Technology, ShanghaiTech University, Shanghai, China
- 4Department of Pulmonary and Critical Care Medicine, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 5Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China
- 6CAS CEMCS-CUHK Joint Laboratory, Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
Abstract
The lung consists of two anatomically distinct compartments: the airways and the alveoli. Although airway epithelial stem cells are known to mobilize for alveolar regeneration, whether alveolar cells can reciprocally traverse these anatomical boundaries and contribute to bronchial repair remains unclear1–4. Here we developed dual-recombinase-mediated lineage-tracing techniques in mice to demonstrate that alveolar type 2 (AT2) cells migrate into injured bronchioles and transdifferentiate into club cells and ciliated cells, thereby actively contributing to airway regeneration. Mechanistically, after bronchial injury, infiltrating immune cells secrete SPP1, establishing a chemotactic gradient directing cell migration. Peribronchiolar AT2 cells sense this SPP1 signal through the integrin ITGB1 and migrate towards the injured bronchioles. On arrival, these migrated AT2 cells receive Notch ligands from resident ciliated cells, leading to Notch pathway activation, which in turn drives their transdifferentiation into club cells. This transdifferentiation process is accompanied by an intermediate stage marked by Cldn4 expression. Functional blockade of either SPP1 or ITGB1 impairs AT2 cell migration, whereas inhibition of Notch signalling prevents their transdifferentiation into club cells. Collectively, our findings reveal a cross-compartmental cellular mechanism for bronchiolar epithelial repair, expanding the current understanding of lung regenerative plasticity and potentially informing therapeutic strategies for airway injury.
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BibTeX
@article{liu2026alveolar,
title = {{Alveolar stem cells transdifferentiate to drive bronchiolar regeneration}},
author = {Kuo Liu and Zixin Liu and Xinfeng Meng and Muxue Tang and Fanglin Di and Zhongxiao Wang and Chenfei Li and Shan Yang and Yanli Zhang and Xueying Yang and Zan Lv and Xufeng Li and Hengwei Jin and Wenjuan Pu and Huan Zhao and Feng Li and Pengfei Sui and Bin Zhou},
journal = {Nature},
year = {2026},
month = oct,
doi = {10.1038/s41586-026-11127-w},
url = {https://doi.org/10.1038/s41586-026-11127-w},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Alveolar stem cells transdifferentiate to drive bronchiolar regeneration
AU - Kuo Liu
AU - Zixin Liu
AU - Xinfeng Meng
AU - Muxue Tang
AU - Fanglin Di
AU - Zhongxiao Wang
AU - Chenfei Li
AU - Shan Yang
AU - Yanli Zhang
AU - Xueying Yang
AU - Zan Lv
AU - Xufeng Li
AU - Hengwei Jin
AU - Wenjuan Pu
AU - Huan Zhao
AU - Feng Li
AU - Pengfei Sui
AU - Bin Zhou
PY - 2026
DA - 2026/10/07
JO - Nature
DO - 10.1038/s41586-026-11127-w
UR - https://doi.org/10.1038/s41586-026-11127-w
AB - The lung consists of two anatomically distinct compartments: the airways and the alveoli. Although airway epithelial stem cells are known to mobilize for alveolar regeneration, whether alveolar cells can reciprocally traverse these anatomical boundaries and contribute to bronchial repair remains unclear1–4. Here we developed dual-recombinase-mediated lineage-tracing techniques in mice to demonstrate that alveolar type 2 (AT2) cells migrate into injured bronchioles and transdifferentiate into club cells and ciliated cells, thereby actively contributing to airway regeneration. Mechanistically, after bronchial injury, infiltrating immune cells secrete SPP1, establishing a chemotactic gradient directing cell migration. Peribronchiolar AT2 cells sense this SPP1 signal through the integrin ITGB1 and migrate towards the injured bronchioles. On arrival, these migrated AT2 cells receive Notch ligands from resident ciliated cells, leading to Notch pathway activation, which in turn drives their transdifferentiation into club cells. This transdifferentiation process is accompanied by an intermediate stage marked by Cldn4 expression. Functional blockade of either SPP1 or ITGB1 impairs AT2 cell migration, whereas inhibition of Notch signalling prevents their transdifferentiation into club cells. Collectively, our findings reveal a cross-compartmental cellular mechanism for bronchiolar epithelial repair, expanding the current understanding of lung regenerative plasticity and potentially informing therapeutic strategies for airway injury.
SN - 0028-0836
SN - 1476-4687
ER -