Article | Published:

Dedifferentiation of committed epithelial cells into stem cells in vivo

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



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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    EntwicklungsphysiologischeStudien. I. Die Regeneration der Urodelenlinse. Arch. Entwickl. Mech. Org. 1, 380–390 (1895)

  2. 2.

    & Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nature Rev. Mol. Cell Biol. 3, 566–574 (2002)

  3. 3.

    & Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004)

  4. 4.

    Metaplasia and transdifferentiation: from pure biology to the clinic. Nature Rev. Mol. Cell Biol. 8, 369–378 (2007)

  5. 5.

    et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460, 60–65 (2009)

  6. 6.

    , & Mouse digit tip regeneration is mediated by fate-restricted progenitor cells. Proc. Natl Acad. Sci. USA 108, 20609–20614 (2011)

  7. 7.

    , , , & Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip. Nature 476, 409–413 (2011)

  8. 8.

    , & Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation? Trends Cell Biol. 21, 212–218 (2011)

  9. 9.

    et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009)

  10. 10.

    et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011)

  11. 11.

    et al. Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464, 606–609 (2010)

  12. 12.

    , & Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nature Rev. Mol. Cell Biol. 12, 79–89 (2011)

  13. 13.

    et al. Dll1+ secretory progenitor cells revert to stem cells upon crypt damage. Nature Cell Biol. 14, 1099–1104 (2012)

  14. 14.

    et al. Liver regeneration and α-fetoprotein messenger RNA expression in the retrorsine model for hepatocyte transplantation. Cancer Res. 58, 5825–5834 (1998)

  15. 15.

    & Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334 (2004)

  16. 16.

    et al. Centrosome misorientation reduces stem cell division during ageing. Nature 456, 599–604 (2008)

  17. 17.

    , , & Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 144, 92–105 (2011)

  18. 18.

    et al. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc. Natl Acad. Sci. USA 109, 17531–17536 (2012)

  19. 19.

    et al. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525–534 (2009)

  20. 20.

    et al. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc. Natl Acad. Sci. USA 106, 12771–12775 (2009)

  21. 21.

    & Epithelial progenitor cells in lung development, maintenance, repair, and disease. Annu. Rev. Cell Dev. Biol. 27, 493–512 (2011)

  22. 22.

    , , , & Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivatorstTA and rTA linked to the keratin 5 promoter. J. Invest. Dermatol. 115, 788–794 (2000)

  23. 23.

    et al. Inducible gene expression in GFAP+ progenitor cells of the SGZ and the dorsal wall of the SVZ—a novel tool to manipulate and trace adult neurogenesis. Glia 59, 615–626 (2011)

  24. 24.

    et al. Airway specific inducible transgene expression using aerosolized doxycycline. Am. J. Respir. Cell Mol. Biol. (12 July, 2013)

  25. 25.

    et al. V-ATPase B1-subunit promoter drives expression of EGFP in intercalated cells of kidney, clear cells of epididymis and airway cells of lung in transgenic mice. Am. J. Physiol. Cell Physiol. 288, C1134–C1144 (2005)

  26. 26.

    et al. In vivo imaging of tracheal epithelial cells in mice during airway regeneration. Am. J. Respir. Cell Mol. Biol. 47, 864–868 (2012)

  27. 27.

    et al. Enhanced Tim3 activity improves survival after influenza infection. J. Immunol. 189, 2879–2889 (2012)

  28. 28.

    & Transplantation of living nuclei from blastula cells into enucleated frogs’ eggs. Proc. Natl Acad. Sci. USA 38, 455–463 (1952)

  29. 29.

    , & Sexually mature individuals of Xenopus laevis from the transplantation of single somatic nuclei. Nature 182, 64–65 (1958)

  30. 30.

    Tracing the cellular origin of cancer. Nature Cell Biol. 15, 126–134 (2012)

  31. 31.

    et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013)

  32. 32.

    et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338, 1080–1084 (2012)

  33. 33.

    Cells of origin in cancer. Nature 469, 314–322 (2011)

  34. 34.

    , , , & Identification of a cell of origin for human prostate cancer. Science 329, 568–571 (2010)

  35. 35.

    et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011)

Download references


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


  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


  1. Search for Purushothama Rao Tata in:

  2. Search for Hongmei Mou in:

  3. Search for Ana Pardo-Saganta in:

  4. Search for Rui Zhao in:

  5. Search for Mythili Prabhu in:

  6. Search for Brandon M. Law in:

  7. Search for Vladimir Vinarsky in:

  8. Search for Josalyn L. Cho in:

  9. Search for Sylvie Breton in:

  10. Search for Amar Sahay in:

  11. Search for Benjamin D. Medoff in:

  12. Search for Jayaraj Rajagopal in:


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.

Extended data

About this article

Publication history





Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.