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Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche

Nature Medicine volume 13, pages 1219–1227 (2007)Cite this article

Abstract

The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.

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Figure 1: Isolation and characterization of TSPCs.
Figure 2: Multidifferentiation potential of putative mouse and human TSPCs in vitro and in vivo.
Figure 3: Self-renewal of putative tendon stem cells.
Figure 4: Regeneration potential of TSPCs.
Figure 5: The extracellular matrix niche dictates the fate of TSPCs.
Figure 6: Ectopic activation of BMP signaling induces ossification in Bgn−/0Fmod−/− mouse tendon tissue.

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Acknowledgements

This research was supported in part by the Division of Intramural Research, US National Institute of Dental and Craniofacial Research, US National Institutes of Health and by an extramural grant from the US National Institutes of Health (US National Heart, Lung, and Blood Institute R01 HL61589-01 for L.Z.). We thank Å. Oldberg, University of Lund, Sweden for providing Fmod-deficient mice; P. Robey for advice and discussion on this work; H. Wimer, N. Marino, S. Kuznetsov and N. Cherman for technical assistance; and P. Vyomesh for his help with the isolation of mouse dermal fibroblasts.

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Authors and Affiliations

  1. Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, US National Institutes of Health, 30 Convent Dr. 30/225 MSC 4320, Bethesda, Maryland 20892, USA.,

    Yanming Bi, Tina M Kilts, Colette A Inkson, Mildred C Embree, Wataru Sonoyama, Li Li, Byoung-Moo Seo, Songtao Shi & Marian F Young

  2. Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, 800 W. Baltimore Street, Baltimore, 21201, Maryland, USA

    Driss Ehirchiou & Li Zhang

  3. Division of Pediatric Orthopaedics, Johns Hopkins University, 601 N. Caroline Street, Baltimore, 21287, Maryland, USA

    Arabella I Leet

  4. Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, 2250 Alcazar Street, CSA 103, Los Angeles, 90033, California, USA

    Songtao Shi

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  1. Yanming Bi
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Contributions

Y.B. designed and performed the majority of the experiments, analyzed data and prepared the manuscript. D.E. performed, collected and analyzed the FACS data; T.M.K. maintained animals, assisted with in vivo experiments and collected tissue samples; C.A.I. performed nucleofection and luciferase reporter assays; M.C.E. and W.S. assisted with immunohistochemistry staining and L.L. prepared paraffin-embedded tissue sections. A.I.L. provided human samples. B.-M.S. helped with in vitro multipotent differentiation assays and in vivo transplantation. L.Z. designed the FACS analysis and helped with the preparation of the manuscript. S.S. designed the key experiments and prepared the manuscript. M.F.Y. performed RT-PCR and prepared the manuscript.

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Correspondence to Songtao Shi or Marian F Young.

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Bi, Y., Ehirchiou, D., Kilts, T. et al. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med 13, 1219–1227 (2007). https://doi.org/10.1038/nm1630

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