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A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration

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  • Yuki Matsushita

    (University of Michigan School of Dentistry)

  • Mizuki Nagata

    (University of Michigan School of Dentistry)

  • Kenneth M. Kozloff

    (University of Michigan)

  • Joshua D. Welch

    (University of Michigan)

  • Koji Mizuhashi

    (University of Michigan School of Dentistry)

  • Nicha Tokavanich

    (University of Michigan School of Dentistry)

  • Shawn A. Hallett

    (University of Michigan School of Dentistry)

  • Daniel C. Link

    (Washington University School of Medicine, Division of Oncology)

  • Takashi Nagasawa

    (Osaka University School of Medicine, Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences)

  • Wanida Ono

    (University of Michigan School of Dentistry)

  • Noriaki Ono

    (University of Michigan School of Dentistry)

Abstract

Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12). However, how these cells are activated during regeneration and facilitate osteogenesis remains largely unknown. Cell-lineage analysis using Cxcl12-creER mice reveals that quiescent Cxcl12-creER+ perisinusoidal BMSCs differentiate into cortical bone osteoblasts solely during regeneration. A combined single cell RNA-seq analysis demonstrate that these cells convert their identity into a skeletal stem cell-like state in response to injury, associated with upregulation of osteoblast-signature genes and activation of canonical Wnt signaling components along the single-cell trajectory. β-catenin deficiency in these cells indeed causes insufficiency in cortical bone regeneration. Therefore, quiescent Cxcl12-creER+ BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration.

Suggested Citation

  • Yuki Matsushita & Mizuki Nagata & Kenneth M. Kozloff & Joshua D. Welch & Koji Mizuhashi & Nicha Tokavanich & Shawn A. Hallett & Daniel C. Link & Takashi Nagasawa & Wanida Ono & Noriaki Ono, 2020. "A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14029-w
    DOI: 10.1038/s41467-019-14029-w
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    Cited by:

    1. 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.
    2. Yoshiki Omatsu & Shota Aiba & Tomonori Maeta & Kei Higaki & Kazunari Aoki & Hitomi Watanabe & Gen Kondoh & Riko Nishimura & Shu Takeda & Ung-il Chung & Takashi Nagasawa, 2022. "Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Madison L. Doolittle & Dominik Saul & Japneet Kaur & Jennifer L. Rowsey & Stephanie J. Vos & Kevin D. Pavelko & Joshua N. Farr & David G. Monroe & Sundeep Khosla, 2023. "Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Adrienne Anginot & Julie Nguyen & Zeina Abou Nader & Vincent Rondeau & Amélie Bonaud & Maria Kalogeraki & Antoine Boutin & Julia P. Lemos & Valeria Bisio & Joyce Koenen & Lea Hanna Doumit Sakr & Amand, 2023. "WHIM Syndrome-linked CXCR4 mutations drive osteoporosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. 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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