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Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction

Author

Listed:
  • Kotaro Shimizu

    (Osaka University
    Osaka University
    Osaka University)

  • Junichi Kikuta

    (Osaka University
    Osaka University
    National Institutes of Biomedical Innovation, Health and Nutrition)

  • Yumi Ohta

    (Osaka University)

  • Yutaka Uchida

    (Osaka University
    Osaka University)

  • Yu Miyamoto

    (Osaka University
    Osaka University)

  • Akito Morimoto

    (Osaka University
    Osaka University)

  • Shinya Yari

    (Osaka University
    Osaka University)

  • Takashi Sato

    (Osaka University)

  • Takefumi Kamakura

    (Osaka University)

  • Kazuo Oshima

    (Osaka University)

  • Ryusuke Imai

    (Osaka University)

  • Yu-Chen Liu

    (Osaka University
    Osaka University)

  • Daisuke Okuzaki

    (Osaka University
    Osaka University)

  • Tetsuya Hara

    (Kobe Pharmaceutical University)

  • Daisuke Motooka

    (Osaka University
    Osaka University)

  • Noriaki Emoto

    (Kobe Pharmaceutical University)

  • Hidenori Inohara

    (Osaka University)

  • Masaru Ishii

    (Osaka University
    Osaka University
    National Institutes of Biomedical Innovation, Health and Nutrition)

Abstract

Cholesteatoma, which potentially results from tympanic membrane retraction, is characterized by intractable local bone erosion and subsequent hearing loss and brain abscess formation. However, the pathophysiological mechanisms underlying bone destruction remain elusive. Here, we performed a single-cell RNA sequencing analysis on human cholesteatoma samples and identify a pathogenic fibroblast subset characterized by abundant expression of inhibin βA. We demonstrate that activin A, a homodimer of inhibin βA, promotes osteoclast differentiation. Furthermore, the deletion of inhibin βA /activin A in these fibroblasts results in decreased osteoclast differentiation in a murine model of cholesteatoma. Moreover, follistatin, an antagonist of activin A, reduces osteoclastogenesis and resultant bone erosion in cholesteatoma. Collectively, these findings indicate that unique activin A-producing fibroblasts present in human cholesteatoma tissues are accountable for bone destruction via the induction of local osteoclastogenesis, suggesting a potential therapeutic target.

Suggested Citation

  • Kotaro Shimizu & Junichi Kikuta & Yumi Ohta & Yutaka Uchida & Yu Miyamoto & Akito Morimoto & Shinya Yari & Takashi Sato & Takefumi Kamakura & Kazuo Oshima & Ryusuke Imai & Yu-Chen Liu & Daisuke Okuzak, 2023. "Single-cell transcriptomics of human cholesteatoma identifies an activin A-producing osteoclastogenic fibroblast subset inducing bone destruction," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40094-3
    DOI: 10.1038/s41467-023-40094-3
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    References listed on IDEAS

    as
    1. Matthew B. Buechler & Rachana N. Pradhan & Akshay T. Krishnamurty & Christian Cox & Aslihan Karabacak Calviello & Amber W. Wang & Yeqing Angela Yang & Lucinda Tam & Roger Caothien & Merone Roose-Girma, 2021. "Cross-tissue organization of the fibroblast lineage," Nature, Nature, vol. 593(7860), pages 575-579, May.
    2. Junyue Cao & Malte Spielmann & Xiaojie Qiu & Xingfan Huang & Daniel M. Ibrahim & Andrew J. Hill & Fan Zhang & Stefan Mundlos & Lena Christiansen & Frank J. Steemers & Cole Trapnell & Jay Shendure, 2019. "The single-cell transcriptional landscape of mammalian organogenesis," Nature, Nature, vol. 566(7745), pages 496-502, February.
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