Abstract

Mesenchymal stem cells occupy niches in stromal tissues where they provide sources of cells for specialized mesenchymal derivatives during growth and repair1. The origins of mesenchymal stem cells have been the subject of considerable discussion, and current consensus holds that perivascular cells form mesenchymal stem cells in most tissues. The continuously growing mouse incisor tooth offers an excellent model to address the origin of mesenchymal stem cells. These stem cells dwell in a niche at the tooth apex where they produce a variety of differentiated derivatives. Cells constituting the tooth are mostly derived from two embryonic sources: neural crest ectomesenchyme and ectodermal epithelium2. It has been thought for decades that the dental mesenchymal stem cells3 giving rise to pulp cells and odontoblasts derive from neural crest cells after their migration in the early head and formation of ectomesenchymal tissue4,5. Here we show that a significant population of mesenchymal stem cells during development, self-renewal and repair of a tooth are derived from peripheral nerve-associated glia. Glial cells generate multipotent mesenchymal stem cells that produce pulp cells and odontoblasts. By combining a clonal colour-coding technique6 with tracing of peripheral glia, we provide new insights into the dynamics of tooth organogenesis and growth.

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Acknowledgements

P. Kovaleva and O. Rogachevskaya helped with illustrations. This study was supported by the Swedish Research Council (I.A., K.F., P.E.), The Bertil Hållsten Research Foundation (I.A.), StratRegen and the Wallenberg Foundation (CLICK, I.A.), the Swiss National Science Foundation (U.S.), Medical Research Council (G0901599; P.S.), a Wallenberg Scholar and European Research Council advanced grant (P.E.), National Graduate School in Odontological Science (M.K.S.), the Swedish Dental Association (N.K., M.K.S.), an EMBO Long-Term Fellowship (M.K.) and Stockholm County Council (N.K.) and Developmental Studies Hybridoma Bank.

Author information

Author notes

    • Nina Kaukua
    •  & Maryam Khatibi Shahidi

    These authors contributed equally to this work.

Affiliations

  1. Department of Neuroscience, Karolinska Institutet, Stockholm 17177, Sweden

    • Nina Kaukua
    •  & Kaj Fried
  2. Department of Dental Medicine, Karolinska Institutet, Stockholm 17177, Sweden

    • Maryam Khatibi Shahidi
  3. Division of Molecular Neurobiology, MRC National Institute for Medical Research, London NW7 1AA, UK

    • Chrysoula Konstantinidou
    •  & Vassilis Pachnis
  4. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden

    • Vyacheslav Dyachuk
    • , Marketa Kaucka
    •  & Igor Adameyko
  5. A.V. Zhirmunsky Institute of Marine Biology of the Far Eastern Branch of the Russian Academy of Sciences, Vladivostok 690041, Russia

    • Vyacheslav Dyachuk
  6. Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm 17177, Sweden

    • Alessandro Furlan
    • , Natalia Assaife Lopes
    •  & Patrik Ernfors
  7. Department of Craniofacial Development and Stem Cell Biology, King’s College London Dental Institute, Guy’s Hospital, London SE1 3QD, UK

    • Zhengwen An
    • , Longlong Wang
    •  & Paul Sharpe
  8. Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm 17177, Sweden

    • Isabell Hultman
    •  & Lars Ährlund-Richter
  9. Science for Life Laboratory, Royal Institute of Technology, Stockholm 17177, Sweden

    • Hans Blom
    •  & Hjalmar Brismar
  10. Department of Biology, Institute of Molecular Health Sciences, ETH Zurich CH-8093, Switzerland

    • Ueli Suter
  11. Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen (KNAW), PO Box 85164, 3508 AD Utrecht, the Netherlands

    • Hans Clevers
  12. Department of Molecular Genetics, University Medical Center Utrecht, Utrecht 3508 GA, the Netherlands

    • Hans Clevers
  13. Institute of Biotechnology, Developmental Biology Program, University of Helsinki, Helsinki FI-00014, Finland

    • Irma Thesleff

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Contributions

N.K., M.K.S., C.K., V.D., M.K., A.F., Z.A., L.W., P.S., I.H., I.A. and K.F. performed experiments, analysed data and wrote the paper. L.A.-R., H.B., H.B., N.A.L., V.P., U.S., H.C., P.S., I.T. and P.E. analysed data and wrote the paper. All authors read and approved the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Kaj Fried or Igor Adameyko.

Extended data

Supplementary information

Videos

  1. 1.

    In situ hybridization reveals Thy1 expression in apical region of incisor

    Optical projection tomography video showing expression pattern of Thy1 in adult mouse incisor. Note specific localization of Thy1 at the tooth apex.

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DOI

https://doi.org/10.1038/nature13536

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