Letter | Published:

p63+Krt5+ distal airway stem cells are essential for lung regeneration

Nature volume 517, pages 616620 (29 January 2015) | Download Citation

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Abstract

Lung diseases such as chronic obstructive pulmonary disease1 and pulmonary fibrosis2 involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia3,4 or acute respiratory distress syndrome5,6 often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASCp63/Krt5, to this process7. Here we show that pre-existing, intrinsically committed DASCp63/Krt5 undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASCp63/Krt5 in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASCp63/Krt5-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.

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Acknowledgements

This work was supported by grants from the Joint Council Office of the Agency for Science Technology Research Agency (ASTAR), Singapore (W.X., F.M.), Defense Advanced Research Projects Agency (DARPA, N66001-09-1-2121 to F.M.), the Johnson & Johnson ASTAR Joint Program (W.X., F.M.) and support from Connecticut Innovations (W.X., F.M.). We thank M. LaLande, B. Lane and H. Hui Ng for support, G. Wright, B. Tennent, B. Knowles and T. McLaughlin for comments on the manuscript, J. Hammer for artwork, P. Kraus for blastocyst injections, and H. Ahmad and K. L. Goh for technical assistance. We thank H. Green for advice and support.

Author information

Affiliations

  1. Genome Institute of Singapore, A-STAR, 138672 Singapore

    • Wei Zuo
    • , Ting Zhang
    • , Daniel Zheng'An Wu
    • , Shou Ping Guan
    • , Audrey-Ann Liew
    • , Siew Joo Lim
    • , Wa Xian
    •  & Frank McKeon
  2. The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA

    • Yusuke Yamamoto
    • , Xia Wang
    • , Wa Xian
    •  & Frank McKeon
  3. Advanced Cell Technologies, Marlborough, Massachusetts 01752, USA

    • Matthew Vincent
  4. The Jackson Laboratory, Bar Harbor, Maine 04609, USA

    • Mark Lessard
  5. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Christopher P. Crum
    •  & Wa Xian
  6. Department of Medicine, National University Health System, 119228 Singapore

    • Wa Xian
    •  & Frank McKeon
  7. Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA

    • Wa Xian

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Contributions

Experiments were performed by W.Z., D.Z.W., S.P.G. and A.-A.L. Experimental design and conception were done by W.Z., M.V., C.P.C., W.X. and F.M.; T.Z., W.Z., X.W., S.J.L. and Y.Y. performed microarrays and computational analysis, and provided methodological advice. M.L. and W.Z. performed the serial reconstructions of infected lung.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Wa Xian or Frank McKeon.

Datasets generated for this study have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database under superseries GSE60849.

Extended data

Supplementary information

Videos

  1. 1.

    Reconstruction of 3-D pattern of Krt5 staining with respect to bronchioles (blue) in portion of 15dpi infected lung from serial sections.

    Reconstruction of 3-D pattern of Krt5 staining with respect to bronchioles (blue) in portion of 15dpi infected lung from serial sections.

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DOI

https://doi.org/10.1038/nature13903

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