Functional Characterization of Quiescent Keratinocyte Stem Cells and Their Progeny Reveals a Hierarchical Organization in Human Skin Epidermis§

Authors

  • Holger Schlüter,

    1. Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, Melbourne, Victoria, Australia
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  • Sophie Paquet-Fifield,

    1. Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, Melbourne, Victoria, Australia
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  • Pradnya Gangatirkar,

    1. Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, Melbourne, Victoria, Australia
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  • Jason Li,

    1. Bioinformatics Core Facility, Research Division, Peter MacCallum Cancer Centre, St Andrew's Place, Melbourne, Victoria, Australia
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  • Pritinder Kaur

    Corresponding author
    1. Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, Melbourne, Victoria, Australia
    • Epithelial Stem Cell Biology Laboratory, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, Victoria 3002, Australia
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    • Telephone: 61-3-9656-3714; Fax: 61-3-9656-1411


  • Author contributions: H.S.: collection and assembly of data; data analysis and interpretation, manuscript writing; S.P.-F.: collection and assembly of data, data analysis and interpretation; P.G.: collection and assembly of data; J.L.: bioinformatic analyses of microarray data analysis; P.K.: conception and design, collection and assembly of data; data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS June 14, 2011.

Abstract

Although homeostatic renewal of human skin epidermis is achieved by the combined activity of quiescent stem cells (SCs) and their actively cycling progeny, whether these two populations are equipotent in their capacity to regenerate tissue has not been determined in biological assays that mimic lifelong renewal. Using fluorescence activated cell separation strategy validated previously by us, human epidermis was fractionated into three distinct subsets: that is, αmath imageCD71dim, αmath imageCD71bri, and αmath image with characteristics of keratinocyte stem, transient amplifying, and early differentiating cells, respectively. The global gene expression profile of these fractions was determined by microarray, confirming that the αmath imageCD71dim subset was quiescent, the αmath imageCD71bri was actively cycling, and the αmath image subset expressed markers of differentiation. More importantly, functional evaluation of these populations in an in vivo model for tissue reconstitution at limiting cell dilutions revealed that the quiescent αmath imageCD71dim fraction was the most potent proliferative and tissue regenerative population of the epidermis, capable of long-term (LT) epidermal renewal from as little as 100 cells for up to 10 weeks. In contrast, the cycling αmath imageCD71bri fraction was the first to initiate tissue reconstitution, although this was not sustained in the LT, while differentiating αmath image cells possessed the lowest demonstrable tissue regenerative capacity. Our data suggest that in human skin, the epidermal proliferative compartment is not composed of equipotent cells, but rather is organized in a functionally hierarchical manner with the most potent quiescent SCs at its apex (i.e., αmath imageCD71dim) followed by cycling progenitors (i.e., αmath imageCD71bri) and finally early differentiating keratinocytes (i.e., αmath image). STEM CELLS 2011;29:1256–1268

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