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A single type of progenitor cell maintains normal epidermis

Abstract

According to the current model of adult epidermal homeostasis, skin tissue is maintained by two discrete populations of progenitor cells: self-renewing stem cells; and their progeny, known as transit amplifying cells, which differentiate after several rounds of cell division1,2,3. By making use of inducible genetic labelling, we have tracked the fate of a representative sample of progenitor cells in mouse tail epidermis at single-cell resolution in vivo at time intervals up to one year. Here we show that clone-size distributions are consistent with a new model of homeostasis involving only one type of progenitor cell. These cells are found to undergo both symmetric and asymmetric division at rates that ensure epidermal homeostasis. The results raise important questions about the potential role of stem cells on tissue maintenance in vivo.

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Figure 1: In vivo clonal labelling of epidermal progenitor cells.
Figure 2: Clone fate data.
Figure 3: Asymmetric cell fate in epidermal progenitors.
Figure 4: Scaling and model of epidermal progenitor cell fate.

References

  1. 1

    Lajtha, L. G. Stem cell concepts. Differentiation 14, 23–34 (1979)

    CAS  Article  Google Scholar 

  2. 2

    Alonso, L. & Fuchs, E. Stem cells of the skin epithelium. Proc. Natl Acad. Sci. USA 100, (suppl. 1)11830–11835 (2003)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Braun, K. M. & Watt, F. M. Epidermal label-retaining cells: background and recent applications. J. Invest. Dermatol. Symp. Proc. 9, 196–201 (2004)

    Article  Google Scholar 

  4. 4

    Gambardella, L. & Barrandon, Y. The multifaceted adult epidermal stem cell. Curr. Opin. Cell Biol. 15, 771–777 (2003)

    CAS  Article  Google Scholar 

  5. 5

    Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22, 411–417 (2004)

    CAS  Article  Google Scholar 

  7. 7

    Levy, V., Lindon, C., Harfe, B. D. & Morgan, B. A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005)

    CAS  Article  Google Scholar 

  8. 8

    Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351–1354 (2005)

    CAS  Article  Google Scholar 

  9. 9

    Claudinot, S., Nicolas, M., Oshima, H., Rochat, A. & Barrandon, Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc. Natl Acad. Sci. USA 102, 14677–14682 (2005)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Mackenzie, I. C. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature 226, 653–655 (1970)

    ADS  CAS  Article  Google Scholar 

  11. 11

    Potten, C. S. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 7, 77–88 (1974)

    CAS  PubMed  Google Scholar 

  12. 12

    Ghazizadeh, S. & Taichman, L. B. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 20, 1215–1222 (2001)

    CAS  Article  Google Scholar 

  13. 13

    Kameda, T. et al. Analysis of the cellular heterogeneity in the basal layer of mouse ear epidermis: an approach from partial decomposition in vitro and retroviral cell marking in vivo. Exp. Cell Res. 283, 167–183 (2003)

    CAS  Article  Google Scholar 

  14. 14

    Ro, S. & Rannala, B. A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation. EMBO Rep. 5, 914–920 (2004)

    CAS  Article  Google Scholar 

  15. 15

    Ro, S. & Rannala, B. Evidence from the stop-EGFP mouse supports a niche-sharing model of epidermal proliferative units. Exp. Dermatol. 14, 838–843 (2005)

    Article  Google Scholar 

  16. 16

    Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001)

    CAS  Article  Google Scholar 

  17. 17

    Kemp, R. et al. Elimination of background recombination: somatic induction of Cre by combined transcriptional regulation and hormone binding affinity. Nucleic Acids Res. 32, e92 (2004)

    Article  Google Scholar 

  18. 18

    Braun, K. M. et al. Manipulation of stem cell proliferation and lineage commitment: visualisation of label-retaining cells in wholemounts of mouse epidermis. Development 130, 5241–5255 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Williams, G. H. et al. Improved cervical smear assessment using antibodies against proteins that regulate DNA replication. Proc. Natl Acad. Sci. USA 95, 14932–14937 (1998)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Birner, P. et al. Immunohistochemical detection of cell growth fraction in formalin-fixed and paraffin-embedded murine tissue. Am. J. Pathol. 158, 1991–1996 (2001)

    CAS  Article  Google Scholar 

  21. 21

    Potten, C. S. Cell replacement in epidermis (keratopoiesis) via discrete units of proliferation. Int. Rev. Cytol. 69, 271–318 (1981)

    CAS  Article  Google Scholar 

  22. 22

    Das, T., Payer, B., Cayouette, M. & Harris, W. A. In vivo time-lapse imaging of cell divisions during neurogenesis in the developing zebrafish retina. Neuron 37, 597–609 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Gho, M. & Schweisguth, F. Frizzled signalling controls orientation of asymmetric sense organ precursor cell divisions in Drosophila. Nature 393, 178–181 (1998)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Smart, I. H. Variation in the plane of cell cleavage during the process of stratification in the mouse epidermis. Br. J. Dermatol. 82, 276–282 (1970)

    CAS  Article  Google Scholar 

  26. 26

    Zhong, W., Feder, J. N., Jiang, M. M., Jan, L. Y. & Jan, Y. N. Asymmetric localization of a mammalian numb homolog during mouse cortical neurogenesis. Neuron 17, 43–53 (1996)

    CAS  Article  Google Scholar 

  27. 27

    Conboy, I. M. & Rando, T. A. The regulation of Notch signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002)

    CAS  Article  Google Scholar 

  28. 28

    Smart, F. M. & Venkitaraman, A. R. Inhibition of interleukin 7 receptor signaling by antigen receptor assembly. J. Exp. Med. 191, 737–742 (2000)

    CAS  Article  Google Scholar 

  29. 29

    Temple, S. & Raff, M. C. Clonal analysis of oligodendrocyte development in culture: evidence for a developmental clock that counts cell divisions. Cell 44, 773–779 (1986)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Y. Amagase for performing RT–PCR, E. Choolun and R. Walker for technical assistance, S. Penrhyn-Lowe and T. Mills for help with microscopy and R. Laskey, W. Harris, A. Philpott and C. Jones for comments. This work was funded by the Medical Research Council, Association for International Cancer Research and Cancer Research UK.

Author Contributions Experimental work was performed by E.C., D.P.D. and P.H.J., project planning by P.H.J. and D.J.W., biophysical analysis by B.D.S. and A.M.K.

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Correspondence to Philip H. Jones.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information 1

This file contains Supplementary Methods, Supplementary Figures S1-S8 with Legends, Supplementary Table 1 and additional results. This section contains additional experimental methods, clone size data for back skin epidermis, the fate of differentiated clones, analysis of tissue growth, cell proliferation, cell migration, apoptosis and mitotic spindle orientation in tail epidermis. (PDF 1780 kb)

Supplementary Information 2

This file contains Supplementary Discussion and Supplementary Figures S9-S11 with Legends. This section contains a detailed analysis of why previous models do not explain the present data, and the derivation of the single compartment model of the epidermis. (PDF 253 kb)

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Clayton, E., Doupé, D., Klein, A. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007). https://doi.org/10.1038/nature05574

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