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Resting zone of the growth plate houses a unique class of skeletal stem cells

Author

Listed:
  • Koji Mizuhashi

    (University of Michigan School of Dentistry)

  • Wanida Ono

    (University of Michigan School of Dentistry)

  • Yuki Matsushita

    (University of Michigan School of Dentistry)

  • Naoko Sakagami

    (University of Michigan School of Dentistry)

  • Akira Takahashi

    (University of Michigan School of Dentistry)

  • Thomas L. Saunders

    (University of Michigan Medical School)

  • Takashi Nagasawa

    (Graduate School of Frontier Biosciences, Osaka University School of Medicine)

  • Henry M. Kronenberg

    (Endocrine Unit, Massachusetts General Hospital and Harvard Medical School)

  • Noriaki Ono

    (University of Michigan School of Dentistry)

Abstract

Skeletal stem cells regulate bone growth and homeostasis by generating diverse cell types, including chondrocytes, osteoblasts and marrow stromal cells. The emerging concept postulates that there exists a distinct type of skeletal stem cell that is closely associated with the growth plate1–4, which is a type of cartilaginous tissue that has critical roles in bone elongation5. The resting zone maintains the growth plate by expressing parathyroid hormone-related protein (PTHrP), which interacts with Indian hedgehog (Ihh) that is released from the hypertrophic zone6–10, and provides a source of other chondrocytes11. However, the identity of skeletal stem cells and how they are maintained in the growth plate are unknown. Here we show, in a mouse model, that skeletal stem cells are formed among PTHrP-positive chondrocytes within the resting zone of the postnatal growth plate. PTHrP-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell-lineage analysis revealed that PTHrP-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit-amplifying chondrocytes in the proliferating zone—which was concertedly maintained by a forward signal from undifferentiated cells (PTHrP) and a reverse signal from hypertrophic cells (Ihh)—provided instructive cues to maintain the cell fates of PTHrP-positive chondrocytes in the resting zone. Our findings unravel a type of somatic stem cell that is initially unipotent and acquires multipotency at the post-mitotic stage, underscoring the malleable nature of the skeletal cell lineage. This system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system.

Suggested Citation

  • Koji Mizuhashi & Wanida Ono & Yuki Matsushita & Naoko Sakagami & Akira Takahashi & Thomas L. Saunders & Takashi Nagasawa & Henry M. Kronenberg & Noriaki Ono, 2018. "Resting zone of the growth plate houses a unique class of skeletal stem cells," Nature, Nature, vol. 563(7730), pages 254-258, November.
    • Handle: RePEc:nat:nature:v:563:y:2018:i:7730:d:10.1038_s41586-018-0662-5
    DOI: 10.1038/s41586-018-0662-5
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    Citations

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    Cited by:

    1. Aaron Warren & Ryan M. Porter & Olivia Reyes-Castro & Md Mohsin Ali & Adriana Marques-Carvalho & Ha-Neui Kim & Landon B. Gatrell & Ernestina Schipani & Intawat Nookaew & Charles A. O’Brien & Roy Morel, 2023. "The NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Yuki Matsushita & Angel Ka Yan Chu & Chiaki Tsutsumi-Arai & Shion Orikasa & Mizuki Nagata & Sunny Y. Wong & Joshua D. Welch & Wanida Ono & Noriaki Ono, 2022. "The fate of early perichondrial cells in developing bones," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Chee Ho H’ng & Shanika L. Amarasinghe & Boya Zhang & Hojin Chang & Xinli Qu & David R. Powell & Alberto Rosello-Diez, 2024. "Compensatory growth and recovery of cartilage cytoarchitecture after transient cell death in fetal mouse limbs," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Shanmugam Muruganandan & Rachel Pierce & Dian Astari Teguh & Rocio Fuente Perez & Nicole Bell & Brandon Nguyen & Katherine Hohl & Brian D. Snyder & Mark W. Grinstaff & Hannah Alberico & Dori Woods & Y, 2022. "A FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Marketa Kaucka & Alberto Joven Araus & Marketa Tesarova & Joshua D. Currie & Johan Boström & Michaela Kavkova & Julian Petersen & Zeyu Yao & Anass Bouchnita & Andreas Hellander & Tomas Zikmund & Ahmed, 2022. "Altered developmental programs and oriented cell divisions lead to bulky bones during salamander limb regeneration," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Masayuki Tsukasaki & Noriko Komatsu & Takako Negishi-Koga & Nam Cong-Nhat Huynh & Ryunosuke Muro & Yutaro Ando & Yuka Seki & Asuka Terashima & Warunee Pluemsakunthai & Takeshi Nitta & Takashi Nakamura, 2022. "Periosteal stem cells control growth plate stem cells during postnatal skeletal growth," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Cheng-Hai Zhang & Yao Gao & Han-Hwa Hung & Zhu Zhuo & Alan J. Grodzinsky & Andrew B. Lassar, 2022. "Creb5 coordinates synovial joint formation with the genesis of articular cartilage," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Yuki Matsushita & Jialin Liu & Angel Ka Yan Chu & Chiaki Tsutsumi-Arai & Mizuki Nagata & Yuki Arai & Wanida Ono & Kouhei Yamamoto & Thomas L. Saunders & Joshua D. Welch & Noriaki Ono, 2023. "Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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