Article | Published:

Dedifferentiation of committed epithelial cells into stem cells in vivo

Nature volume 503, pages 218223 (14 November 2013) | Download Citation

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Abstract

Cellular plasticity contributes to the regenerative capacity of plants, invertebrates, teleost fishes and amphibians. In vertebrates, differentiated cells are known to revert into replicating progenitors, but these cells do not persist as stable stem cells. Here we present evidence that differentiated airway epithelial cells can revert into stable and functional stem cells in vivo. After the ablation of airway stem cells, we observed a surprising increase in the proliferation of committed secretory cells. Subsequent lineage tracing demonstrated that the luminal secretory cells had dedifferentiated into basal stem cells. Dedifferentiated cells were morphologically indistinguishable from stem cells and they functioned as well as their endogenous counterparts in repairing epithelial injury. Single secretory cells clonally dedifferentiated into multipotent stem cells when they were cultured ex vivo without basal stem cells. By contrast, direct contact with a single basal stem cell was sufficient to prevent secretory cell dedifferentiation. In analogy to classical descriptions of amphibian nuclear reprogramming, the propensity of committed cells to dedifferentiate is inversely correlated to their state of maturity. This capacity of committed cells to dedifferentiate into stem cells may have a more general role in the regeneration of many tissues and in multiple disease states, notably cancer.

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Acknowledgements

The work in this manuscript was supported by a Harvard Stem Cell Institute Seed Grant and a National Institutes of Health-National Heart, Lung, and Blood Institute Early Career Research New Faculty (P30) award (5P30HL101287-02) and a Harvard Stem Cell Institute (HSCI) Junior Investigator Grant to J.R. J.R. is a New York Stem Cell Foundation-Robertson Investigator. We wish to extend our thanks to W. Anderson, Y. Dor, Q. Zhou, A. Brack, J. Galloway and all members of the Rajagopal laboratory for their constructive criticism. We thank the members of the HSCI flow cytometry core facility for help with cell sorting.

Author information

Affiliations

  1. Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA

    • Purushothama Rao Tata
    • , Hongmei Mou
    • , Ana Pardo-Saganta
    • , Rui Zhao
    • , Mythili Prabhu
    • , Brandon M. Law
    • , Vladimir Vinarsky
    • , Amar Sahay
    •  & Jayaraj Rajagopal
  2. Departments of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Purushothama Rao Tata
    • , Hongmei Mou
    • , Ana Pardo-Saganta
    • , Rui Zhao
    • , Mythili Prabhu
    • , Brandon M. Law
    • , Vladimir Vinarsky
    •  & Jayaraj Rajagopal
  3. Department of Internal Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Purushothama Rao Tata
    • , Hongmei Mou
    • , Ana Pardo-Saganta
    • , Rui Zhao
    • , Mythili Prabhu
    • , Brandon M. Law
    • , Vladimir Vinarsky
    • , Josalyn L. Cho
    • , Benjamin D. Medoff
    •  & Jayaraj Rajagopal
  4. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • Purushothama Rao Tata
    • , Hongmei Mou
    • , Ana Pardo-Saganta
    • , Rui Zhao
    • , Mythili Prabhu
    • , Brandon M. Law
    • , Vladimir Vinarsky
    • , Amar Sahay
    •  & Jayaraj Rajagopal
  5. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA

    • Josalyn L. Cho
    •  & Benjamin D. Medoff
  6. Center for Systems Biology, Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02214, USA

    • Sylvie Breton
  7. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Amar Sahay

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Contributions

P.R.T. designed and performed experiments and wrote the manuscript; H.M., A.P.-S., R.Z., M.P., B.M.L. and V.V. performed ex vivo experiments; J.L.C. performed influenza infection experiments; A.S. provided tet(O)DTA mice and edited the manuscript; S.B. provided B1-eGFP mice; B.D.M. reviewed the manuscript; J.R. suggested and co-designed the study and co-wrote the manuscript with P.R.T.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jayaraj Rajagopal.

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DOI

https://doi.org/10.1038/nature12777

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