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Wnt activation in nail epithelium couples nail growth to digit regeneration

Nature volume 499, pages 228–232 (2013)Cite this article

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Abstract

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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Figure 1: Nail stem cells are harboured in the proximal nail matrix.
Figure 2: Epithelial β-catenin is required for nail differentiation.
Figure 3: Nail epithelial β-catenin is required for blastema growth and digit regeneration.
Figure 4: Forced Wnt activation in wound epidermis can overcome the limitation of regeneration after proximal amputation.

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Accession codes

Accessions

Gene Expression Omnibus

Data deposits

Expression information has been submitted to the Gene Expression Omnibus database under accession numbers GSE45494, GSM1105640, GSM1105641, GSM1105642 and GSM1105643.

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Acknowledgements

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.

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Authors and Affiliations

  1. The Ronald O. Perelman Department of Dermatology and the Department of Cell Biology, New York University, School of Medicine, New York, 10016, New York, USA

    Makoto Takeo, Wei Chin Chou, Qi Sun, Wendy Lee, Piul Rabbani, Cynthia Loomis & Mayumi Ito

  2. Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan,

    M. Mark Taketo

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  1. Makoto Takeo
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Contributions

M.T. designed and carried out experiments, interpreted data and wrote the manuscript. W.C.C., P.R. and Q.S. performed experiments and interpreted data. M.M.T. generated β-cateninfl/ex3 mice and interpreted the data. C.L. and W.L. interpreted data. M.I. designed experiments, interpreted data and wrote the manuscript.

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Correspondence to Mayumi Ito.

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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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