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Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding

Abstract

The mammalian hair follicle is a complex ‘mini-organ’ thought to form only during development1; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits2,3, mice4 and even humans fifty years ago5. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented6. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.

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Figure 1: Hair follicle regeneration recapitulates embryonic development.
Figure 2: Regenerated hair follicles originate from non-hair-follicle stem cells.
Figure 3: Functional hair follicle stem cells are re-established in regenerated hair follicles.
Figure 4: Hair follicle neogenesis requires Wnt signalling, and overexpression of Wnt potentiates de novo follicle formation.

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Acknowledgements

This work was supported by US National Institutes of Health and, in part, by a grant from the Pennsylvania Department of Health to G.C. We thank P. Sterling for his comments on the manuscript and L. Ash for preparation of histological sections.

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Correspondence to George Cotsarelis.

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Competing interests

M.I. and G.C. are listed as inventors on a patent application related to wounding-induced hair follicle neogenesis and owned by the University of Pennsylvania. G.C. serves on the scientific advisory board and has equity in Follica, a start up company that has licensed the patent from the University of Pennsylvania

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This file contains Supplementary Tables 1-3 and Supplementary Figures 1-8 with Legends. (PDF 6710 kb)

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Ito, M., Yang, Z., Andl, T. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007). https://doi.org/10.1038/nature05766

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