IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56501-w.html
   My bibliography  Save this article

Cloned airway basal progenitor cells to repair fibrotic lung through re-epithelialization

Author

Listed:
  • Yu Zhao

    (Tongji University
    Tongji University)

  • Yueqing Zhou

    (Regend Therapeutics)

  • Weipan Zhang

    (Tongji University
    Tongji University)

  • Mingzhe Liu

    (Tongji University
    Tongji University)

  • Jun Duan

    (Tongji University
    Tongji University)

  • Xiaopeng Zhang

    (Tongji University
    Tongji University)

  • Qiwang Ma

    (BGI-Shenzhen)

  • Yujia Wang

    (Regend Therapeutics
    Kiangnan Institute of Stem Cell)

  • Yuzhen Zhang

    (Tongji University)

  • Zhongliang Guo

    (Tongji University)

  • Ting Zhang

    (Regend Therapeutics
    Kiangnan Institute of Stem Cell)

  • Wei Zuo

    (Tongji University
    Tongji University
    Regend Therapeutics
    Kiangnan Institute of Stem Cell)

Abstract

Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis (IPF) patients causes high mortality worldwide, with no lung repair approaches available currently. Here we show that in murine and monkey models, the KRT5+ P63+ progenitor cells in airway basal layer can enter the alveolar area post fibrotic injury. Aided with an automated culture system, we clone and characterize airway basal progenitor cells from 44 donors with various lung conditions. Transplantation of human progenitor cells into the mouse lung efficiently re-epithelializes the injured alveolar area, forms new respiratory tract and saccule-like structures, which ameliorates fibrotic lesions and improves survival of mice. Mechanistically, the engrafted human progenitor cells do not function by differentiating into mature alveolar cells in mouse lung; instead, they differentiate into saccular cells expressing multiple tight junction proteins such as CLDN4, which help the lung to re-establish epithelial barriers. Furthermore, by cloning P63+ airway basal progenitors from larger mammals and birds, we construct multiple lung-chimerism animals and uncover the evolutionarily conserved roles of these progenitor cells in lung repair. Overall, our data highlight the fate of airway basal progenitor cells in fibrotic lung and provide a potential therapeutic strategy for pulmonary diseases that lack inherent recovery mechanisms.

Suggested Citation

  • Yu Zhao & Yueqing Zhou & Weipan Zhang & Mingzhe Liu & Jun Duan & Xiaopeng Zhang & Qiwang Ma & Yujia Wang & Yuzhen Zhang & Zhongliang Guo & Ting Zhang & Wei Zuo, 2025. "Cloned airway basal progenitor cells to repair fibrotic lung through re-epithelialization," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56501-w
    DOI: 10.1038/s41467-025-56501-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56501-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-56501-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Wei Zuo & Ting Zhang & Daniel Zheng'An Wu & Shou Ping Guan & Audrey-Ann Liew & Yusuke Yamamoto & Xia Wang & Siew Joo Lim & Matthew Vincent & Mark Lessard & Christopher P. Crum & Wa Xian & Frank McKeon, 2015. "p63+Krt5+ distal airway stem cells are essential for lung regeneration," Nature, Nature, vol. 517(7536), pages 616-620, January.
    2. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
    3. Benedikt Jaeger & Jonas Christian Schupp & Linda Plappert & Oliver Terwolbeck & Nataliia Artysh & Gian Kayser & Peggy Engelhard & Taylor Sterling Adams & Robert Zweigerdt & Henning Kempf & Stefan Lien, 2022. "Airway basal cells show a dedifferentiated KRT17highPhenotype and promote fibrosis in idiopathic pulmonary fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Xia Wang & Yusuke Yamamoto & Lane H. Wilson & Ting Zhang & Brooke E. Howitt & Melissa A. Farrow & Florian Kern & Gang Ning & Yue Hong & Chiea Chuen Khor & Benoit Chevalier & Denis Bertrand & Lingyan W, 2015. "Cloning and variation of ground state intestinal stem cells," Nature, Nature, vol. 522(7555), pages 173-178, June.
    5. William J. Zacharias & David B. Frank & Jarod A. Zepp & Michael P. Morley & Farrah A. Alkhaleel & Jun Kong & Su Zhou & Edward Cantu & Edward E. Morrisey, 2018. "Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor," Nature, Nature, vol. 555(7695), pages 251-255, March.
    6. Andrew E. Vaughan & Alexis N. Brumwell & Ying Xi & Jeffrey E. Gotts & Doug G. Brownfield & Barbara Treutlein & Kevin Tan & Victor Tan & Feng Chun Liu & Mark R. Looney & Michael A. Matthay & Jason R. R, 2015. "Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury," Nature, Nature, vol. 517(7536), pages 621-625, January.
    7. Barbara Treutlein & Doug G. Brownfield & Angela R. Wu & Norma F. Neff & Gary L. Mantalas & F. Hernan Espinoza & Tushar J. Desai & Mark A. Krasnow & Stephen R. Quake, 2014. "Reconstructing lineage hierarchies of the distal lung epithelium using single-cell RNA-seq," Nature, Nature, vol. 509(7500), pages 371-375, May.
    8. Astrid Gillich & Fan Zhang & Colleen G. Farmer & Kyle J. Travaglini & Serena Y. Tan & Mingxia Gu & Bin Zhou & Jeffrey A. Feinstein & Mark A. Krasnow & Ross J. Metzger, 2020. "Capillary cell-type specialization in the alveolus," Nature, Nature, vol. 586(7831), pages 785-789, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Laura Heydemann & Małgorzata Ciurkiewicz & Georg Beythien & Kathrin Becker & Klaus Schughart & Stephanie Stanelle-Bertram & Berfin Schaumburg & Nancy Mounogou-Kouassi & Sebastian Beck & Martin Zickler, 2023. "Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yuanyuan Chen & Reka Toth & Sara Chocarro & Dieter Weichenhan & Joschka Hey & Pavlo Lutsik & Stefan Sawall & Georgios T. Stathopoulos & Christoph Plass & Rocio Sotillo, 2022. "Club cells employ regeneration mechanisms during lung tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Rachel Warren & Kylie Klinkhammer & Handeng Lyu & Joseph Knopp & Tingting Yuan & Changfu Yao & Barry Stripp & Stijn P. De Langhe, 2024. "Cell competition drives bronchiolization and pulmonary fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Zhoufeng Wang & Zhe Li & Kun Zhou & Chengdi Wang & Lili Jiang & Li Zhang & Ying Yang & Wenxin Luo & Wenliang Qiao & Gang Wang & Yinyun Ni & Shuiping Dai & Tingting Guo & Guiyi Ji & Minjie Xu & Yiying , 2021. "Deciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Richard J. Hewitt & Franz Puttur & David C. A. Gaboriau & Frédéric Fercoq & Maryline Fresquet & William J. Traves & Laura L. Yates & Simone A. Walker & Philip L. Molyneaux & Samuel V. Kemp & Andrew G., 2023. "Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Andrew K. Beppu & Juanjuan Zhao & Changfu Yao & Gianni Carraro & Edo Israely & Anna Lucia Coelho & Katherine Drake & Cory M. Hogaboam & William C. Parks & Jay K. Kolls & Barry R. Stripp, 2023. "Epithelial plasticity and innate immune activation promote lung tissue remodeling following respiratory viral infection," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Christopher W. Murray & Jennifer J. Brady & Mingqi Han & Hongchen Cai & Min K. Tsai & Sarah E. Pierce & Ran Cheng & Janos Demeter & David M. Feldser & Peter K. Jackson & David B. Shackelford & Monte M, 2022. "LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. Niina M. Santio & Keerthana Ganesh & Pihla P. Kaipainen & Aleksi Halme & Fatemeh Seyednasrollah & Emad Arbash & Satu Hänninen & Riikka Kivelä & Olli Carpen & Pipsa Saharinen, 2024. "Endothelial Pim3 kinase protects the vascular barrier during lung metastasis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    9. Andrea Toth & Paranthaman Kannan & John Snowball & Matthew Kofron & Joseph A. Wayman & James P. Bridges & Emily R. Miraldi & Daniel Swarr & William J. Zacharias, 2023. "Alveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Laura Heydemann & Małgorzata Ciurkiewicz & Theresa Störk & Isabel Zdora & Kirsten Hülskötter & Katharina Manuela Gregor & Lukas Mathias Michaely & Wencke Reineking & Tom Schreiner & Georg Beythien & A, 2025. "Respiratory long COVID in aged hamsters features impaired lung function post-exercise with bronchiolization and fibrosis," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    11. Sarasa Isobe & Ramesh V. Nair & Helen Y. Kang & Lingli Wang & Jan-Renier Moonen & Tsutomu Shinohara & Aiqin Cao & Shalina Taylor & Shoichiro Otsuki & David P. Marciano & Rebecca L. Harper & Mir S. Adi, 2023. "Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Hua He & Chong Ma & Wei Wei & Haonan Wang & Yutian Lai & Ming Liu & Shenfei Sun & Qing Ma & Jiashuang Lai & Hanxiang Liu & Hanmin Liu & Fei Sun & Xinhua Lin, 2025. "Heparan sulfate regulates myofibroblast heterogeneity and function to mediate niche homeostasis during alveolar morphogenesis," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    13. Qiang Zhang & Sai Ma & Zhengzhi Liu & Bohan Zhu & Zirui Zhou & Gaoshan Li & J. Javier Meana & Javier González-Maeso & Chang Lu, 2023. "Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    14. Moujtaba Y. Kasmani & Paytsar Topchyan & Ashley K. Brown & Ryan J. Brown & Xiaopeng Wu & Yao Chen & Achia Khatun & Donia Alson & Yue Wu & Robert Burns & Chien-Wei Lin & Matthew R. Kudek & Jie Sun & We, 2023. "A spatial sequencing atlas of age-induced changes in the lung during influenza infection," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    15. Agnieska Brazovskaja & Tomás Gomes & Rene Holtackers & Philipp Wahle & Christiane Körner & Zhisong He & Theresa Schaffer & Julian Connor Eckel & René Hänsel & Malgorzata Santel & Makiko Seimiya & Timm, 2024. "Cell atlas of the regenerating human liver after portal vein embolization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    16. Ming-Wen Hu & Dong Won Kim & Sheng Liu & Donald J Zack & Seth Blackshaw & Jiang Qian, 2019. "PanoView: An iterative clustering method for single-cell RNA sequencing data," PLOS Computational Biology, Public Library of Science, vol. 15(8), pages 1-17, August.
    17. Cornelia Fuetterer & Thomas Augustin & Christiane Fuchs, 2020. "Adapted single-cell consensus clustering (adaSC3)," Advances in Data Analysis and Classification, Springer;German Classification Society - Gesellschaft für Klassifikation (GfKl);Japanese Classification Society (JCS);Classification and Data Analysis Group of the Italian Statistical Society (CLADAG);International Federation of Classification Societies (IFCS), vol. 14(4), pages 885-896, December.
    18. Reza Mirzazadeh & Zaneta Andrusivova & Ludvig Larsson & Phillip T. Newton & Leire Alonso Galicia & Xesús M. Abalo & Mahtab Avijgan & Linda Kvastad & Alexandre Denadai-Souza & Nathalie Stakenborg & Ale, 2023. "Spatially resolved transcriptomic profiling of degraded and challenging fresh frozen samples," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    19. Yuma Takano & Jun Suzuki & Kotaro Nomura & Gento Fujii & Junko Zenkoh & Hitomi Kawai & Yuta Kuze & Yukie Kashima & Satoi Nagasawa & Yuka Nakamura & Motohiro Kojima & Katsuya Tsuchihara & Masahide Seki, 2024. "Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    20. Ahmed A. Raslan & Tho X. Pham & Jisu Lee & Konstantinos Kontodimas & Andrew Tilston-Lunel & Jillian Schmottlach & Jeongmin Hong & Taha Dinc & Andreea M. Bujor & Nunzia Caporarello & Aude Thiriot & Ulr, 2024. "Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56501-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.