Letter | Published:

Hedgehog actively maintains adult lung quiescence and regulates repair and regeneration

Nature volume 526, pages 578582 (22 October 2015) | Download Citation

Abstract

Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration1,2,3, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover4,5. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial–mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.

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Primary accessions

Gene Expression Omnibus

Data deposits

The Gene Expression Omnibus accession number for the microarray data produced in these studies is GSE68201.

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Acknowledgements

The authors appreciate the input of M. Kahn, M. Beers and R. Shah in these studies. The authors are grateful to A. Stout and the Department of Cell and Developmental Biology Microscopy Core for help with imaging. These studies were supported by funds from the National Institutes of Health (HL110942, HL100405, HL087825 to E.E.M). T.P. is supported by the American Heart Association Fellow-to-Faculty Transition Award, Actelion ENTELLIGENCE Award, and K08-HL121146.

Author information

Author notes

    • Tien Peng

    Present address: University of California, San Francisco, 513 Parnassus Avenue, HSE Building, Room 1312, Box 0130, San Francisco, California 94143, USA (T.P.).

Affiliations

  1. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Tien Peng
    • , Michael P. Morley
    • , Komal S. Rathi
    •  & Edward E. Morrisey
  2. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • David B. Frank
  3. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Rachel S. Kadzik
    •  & Edward E. Morrisey
  4. Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Michael P. Morley
    • , Komal S. Rathi
    •  & Edward E. Morrisey
  5. Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Michael P. Morley
    • , Komal S. Rathi
    • , Tao Wang
    • , Su Zhou
    • , Lan Cheng
    • , Min Min Lu
    •  & Edward E. Morrisey
  6. Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Edward E. Morrisey

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Contributions

T.P. and E.E.M. designed the overall experimental strategy. T.P. and R.S.K. performed lineage tracing and animal injury experiments. T.P. and D.B.F. performed in vitro BrdU and organoid experiments. T.W. performed right heart catheterization on the animals. S.Z., L.C. and M.M.L. performed histology and immunohistochemistry. T.P., D.B.F., K.S.R., M.P.M. and E.E.M. analysed the data. T.P. and E.E.M. wrote and edited the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tien Peng or Edward E. Morrisey.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table shows GO enrichment analysis for microarray analysis in Extended Data Figure 4. GO analysis was performed on the microarray data obtained from activation of Smo in isolated lung mesenchymal cells. The top 10 (by P value significance) categories identified are shown.

  2. 2.

    Supplementary Table 2

    This table contains a list of differentially expressed genes found in the GO category of mitotic nuclear division obtained from activation of Smo in lung mesenchymal cells.

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DOI

https://doi.org/10.1038/nature14984

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