Tracing the origin of alveolar stem cells in lung repair and regeneration

Kuo Liu; Xinfeng Meng; Zixin Liu; Muxue Tang; Zan Lv; Xiuzhen Huang; Hengwei Jin; Ximeng Han; Xiuxiu Liu; Wenjuan Pu; Huan Zhu; Bin Zhou

doi:10.1016/j.cell.2024.03.010

Tracing the origin of alveolar stem cells in lung repair and regeneration

Cell. 2024 Mar 27:S0092-8674(24)00302-7. doi: 10.1016/j.cell.2024.03.010. Online ahead of print.

Authors

Kuo Liu¹, Xinfeng Meng², Zixin Liu³, Muxue Tang³, Zan Lv³, Xiuzhen Huang³, Hengwei Jin³, Ximeng Han³, Xiuxiu Liu³, Wenjuan Pu³, Huan Zhu³, Bin Zhou⁴

Affiliations

¹ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; New Cornerstone Investigator Institute, 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 200031, China.
² School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
³ New Cornerstone Investigator Institute, 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 200031, China.
⁴ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; New Cornerstone Investigator Institute, 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 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: zhoubin@sibs.ac.cn.

PMID: 38579712
DOI: 10.1016/j.cell.2024.03.010

Abstract

Alveolar type 2 (AT2) cells are stem cells of the alveolar epithelia. Previous genetic lineage tracing studies reported multiple cellular origins for AT2 cells after injury. However, conventional lineage tracing based on Cre-loxP has the limitation of non-specific labeling. Here, we introduced a dual recombinase-mediated intersectional genetic lineage tracing approach, enabling precise investigation of AT2 cellular origins during lung homeostasis, injury, and repair. We found AT1 cells, being terminally differentiated, did not contribute to AT2 cells after lung injury and repair. Distinctive yet simultaneous labeling of club cells, bronchioalveolar stem cells (BASCs), and existing AT2 cells revealed the exact contribution of each to AT2 cells post-injury. Mechanistically, Notch signaling inhibition promotes BASCs but impairs club cells' ability to generate AT2 cells during lung repair. This intersectional genetic lineage tracing strategy with enhanced precision allowed us to elucidate the physiological role of various epithelial cell types in alveolar regeneration following injury.

Keywords: AT1 cell; AT2 cell; Notch signaling; bronchioalveolar stem cell; club cell; dual recombinases; genetic tracing; lung regeneration.