The tips of mammalian digits can regenerate after amputation1,2, like those of amphibians. It is unknown why this capacity is limited to the area associated with the nail2,3,4. Here we show that nail stem cells (NSCs) reside in the proximal nail matrix and that the mechanisms governing NSC differentiation are coupled directly with their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, β-catenin stabilization in the NSC region induced their regeneration. These results establish a link between NSC differentiation and digit regeneration, and suggest that NSCs may have the potential to contribute to the development of novel treatments for amputees.
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We thank T. Andl, T. Endo, L. Miller, P. Myung, M. Schober and T. T. Sun for invaluable suggestions and discussion. We thank T. Endo for demonstrating the method of bead implantation. We thank T. T. Sun for the AE13 antibody, K. Muneoka for the Bmp4 plasmid, and A. Mansukhani for 3T3 cells. We thank the Genome Technology Center at NYU (National Institutes of Health (NIH) grant 5P30CA0016087-32 and P30 CA016087-30), and the Center for Functional Genomics at University at Albany for carrying out microarray analyses. We thank F. Liang at the NYU Microscopy Core for transmission electron microscopy (TEM) analysis. We thank the NYU Microscopy Core for the use of a confocal microscope (NCRRS10 RR023704-01A1). M.T. is supported by the NYU Kimmel Stem Cell Center and NYSTEM training grant C026880. M.I. is supported by NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grant 1R01AR059768-01A1, the Ellison Medical Foundation and funding from the Department of Dermatology and Cell Biology, and the Helen and Martin Kimmel Center for Stem Cell Biology, at NYU.
The authors declare no competing financial interests.
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Takeo, M., Chou, W., Sun, Q. et al. Wnt activation in nail epithelium couples nail growth to digit regeneration. Nature 499, 228–232 (2013). https://doi.org/10.1038/nature12214
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