Article | Published:

Lgr5 marks cycling, yet long-lived, hair follicle stem cells

Nature Genetics volume 40, pages 12911299 (2008) | Download Citation

Abstract

In mouse hair follicles, a group of quiescent cells in the bulge is believed to have stem cell activity. Lgr5, a marker of intestinal stem cells, is expressed in actively cycling cells in the bulge and secondary germ of telogen hair follicles and in the lower outer root sheath of anagen hair follicles. Here we show that Lgr5+ cells comprise an actively proliferating and multipotent stem cell population able to give rise to new hair follicles and maintain all cell lineages of the hair follicle over long periods of time. Lgr5+ progeny repopulate other stem cell compartments in the hair follicle, supporting the existence of a stem or progenitor cell hierarchy. By marking Lgr5+ cells during trafficking through the lower outer root sheath, we show that these cells retain stem cell properties and contribute to hair follicle growth during the next anagen. Expression analysis suggests involvement of autocrine Hedgehog signaling in maintaining the Lgr5+ stem cell population.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & The hair cycle. J. Cell Sci. 119, 391–393 (2006).

  2. 2.

    , & Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329–1337 (1990).

  3. 3.

    , , , & Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

  4. 4.

    et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J. Invest. Dermatol. 120, 501–511 (2003).

  5. 5.

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

  6. 6.

    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).

  7. 7.

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

  8. 8.

    , , & Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen. Differentiation 72, 548–557 (2004).

  9. 9.

    et al. The cell-surface marker MTS24 identifies a novel population of follicular keratinocytes with characteristics of progenitor cells. Development 133, 3027–3037 (2006).

  10. 10.

    , , , & Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104, 233–245 (2001).

  11. 11.

    et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

  12. 12.

    , & Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol. Endocrinol. 12, 1830–1845 (1998).

  13. 13.

    et al. The intestinal Wnt/TCF signature. Gastroenterology 132, 628–632 (2007).

  14. 14.

    et al. The β-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241–250 (2002).

  15. 15.

    & Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).

  16. 16.

    et al. Comprehensive microarray transcriptome profiling of CD34-enriched mouse keratinocyte stem cells. J. Invest. Dermatol. 127, 2904–2907 (2007).

  17. 17.

    et al. Improved FACS-Gal: flow cytometric analysis and sorting of viable eukaryotic cells expressing reporter gene constructs. Cytometry 12, 291–301 (1991).

  18. 18.

    et al. Identification of Plet-1 as a specific marker of early thymic epithelial progenitor cells. Proc. Natl. Acad. Sci. USA 105, 961–966 (2008).

  19. 19.

    , & Murine epidermal label-retaining cells isolated by flow cytometry do not express the stem cell markers CD34, Sca-1, or Flk-1. J. Invest. Dermatol. 117, 943–948 (2001).

  20. 20.

    et al. A distinct population of clonogenic and multipotent murine follicular keratinocytes residing in the upper isthmus. J. Cell Sci. 121, 609–617 (2008).

  21. 21.

    , , , & Side population cells in human and mouse epidermis lack stem cell characteristics. Exp. Cell Res. 295, 79–90 (2004).

  22. 22.

    Skin stem cells: rising to the surface. J. Cell Biol. 180, 273–284 (2008).

  23. 23.

    et al. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc. Natl. Acad. Sci. USA 97, 3438–3443 (2000).

  24. 24.

    et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

  25. 25.

    et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).

  26. 26.

    , , & Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124, 2537–2552 (1997).

  27. 27.

    , , , & Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

  28. 28.

    et al. Quantitative proliferation dynamics and random chromosome segregation of hair follicle stem cells. EMBO J. 27, 1309–1320 (2008).

  29. 29.

    , , , & Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Natl. Acad. Sci. USA 104, 10063–10068 (2007).

  30. 30.

    , & Contribution of olfactory neural stem cells to tissue maintenance and regeneration. Nat. Neurosci. 10, 720–726 (2007).

  31. 31.

    The coat of the mouse (Mus musculus). J. Genet. 16, 278–330 (1925).

  32. 32.

    , & Critical stages of hair development and pigmentation in the mouse. Physiol. Zool. 24, 1–8 (1951).

  33. 33.

    et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).

  34. 34.

    et al. Genetic mosaic analysis indicates that the bulb region of coat hair follicles contains a resident population of several active multipotent epithelial lineage progenitors. Dev. Biol. 242, 44–57 (2002).

  35. 35.

    & Method for the harvest and assay of in vitro clonogenic keratinocytes stem cells from mice. Methods Mol. Biol. 289, 79–86 (2005).

Download references

Acknowledgements

We thank D. Roop and W. Buitrago for help with setting up the keratinocyte transplantation assay; Å.-L. Dackland for help with cell sorting; Å. Bergström and I. Sur for contributions during work with animals and preparation of samples; and M. van den Born, M. Cozijnsen and H. Begthel for help with histological procedures. This work was supported by the Swedish Cancer Society (to R.T.), the Swedish Research Council (to R.T.), the National Institutes of Health (AR47898 and U01CA105491 to R.T.), Genmab BV (to H.C.), Koninklijke Nederlandse Akademie van Wetenschappen (to H.C.), Koningin Wilhelmina Fonds (to H.C.), the Louis Jeantet Foundation (to H.C.), an International Agency for Research on Cancer Research Training Fellowship (to V.J.), a Marie-Curie Intra-European Fellowship (to V.J.) and a fellowship from the Wenner-Gren Foundation (M.K.).

Author information

Author notes

    • Viljar Jaks
    • , Nick Barker
    •  & Maria Kasper

    These authors contributed equally to this work.

Affiliations

  1. Karolinska Institutet, Department of Biosciences and Nutrition, Novum, SE-141 57 Huddinge, Sweden.

    • Viljar Jaks
    • , Maria Kasper
    •  & Rune Toftgård
  2. University of Tartu, Institute of Molecular and Cell Biology and Estonian Biocentre, Riia 23, 51010 Tartu, Estonia.

    • Viljar Jaks
  3. Hubrecht Institute, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.

    • Nick Barker
    • , Johan H van Es
    • , Hugo J Snippert
    •  & Hans Clevers

Authors

  1. Search for Viljar Jaks in:

  2. Search for Nick Barker in:

  3. Search for Maria Kasper in:

  4. Search for Johan H van Es in:

  5. Search for Hugo J Snippert in:

  6. Search for Hans Clevers in:

  7. Search for Rune Toftgård in:

Corresponding authors

Correspondence to Hans Clevers or Rune Toftgård.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5 and Supplementary Tables 1–3

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.239

Further reading