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Recapitulating the human segmentation clock with pluripotent stem cells

Author

Listed:
  • Mitsuhiro Matsuda

    (RIKEN Center for Biosystems Dynamics Research (RIKEN BDR)
    European Molecular Biology Laboratory (EMBL) Barcelona)

  • Yoshihiro Yamanaka

    (Kyoto University
    Kyoto University)

  • Maya Uemura

    (Kyoto University
    Kyoto University)

  • Mitsujiro Osawa

    (Kyoto University)

  • Megumu K. Saito

    (Kyoto University)

  • Ayako Nagahashi

    (Kyoto University)

  • Megumi Nishio

    (Kyoto University)

  • Long Guo

    (RIKEN Center for Integrative Medical Sciences (RIKEN IMS))

  • Shiro Ikegawa

    (RIKEN Center for Integrative Medical Sciences (RIKEN IMS))

  • Satoko Sakurai

    (Kyoto University)

  • Shunsuke Kihara

    (Kyoto University)

  • Thomas L. Maurissen

    (Kyoto University)

  • Michiko Nakamura

    (Kyoto University)

  • Tomoko Matsumoto

    (Kyoto University)

  • Hiroyuki Yoshitomi

    (Kyoto University
    Kyoto University)

  • Makoto Ikeya

    (Kyoto University)

  • Noriaki Kawakami

    (Meijo Hospital)

  • Takuya Yamamoto

    (Kyoto University
    Kyoto University
    AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku
    RIKEN Center for Advanced Intelligence Project (AIP))

  • Knut Woltjen

    (Kyoto University)

  • Miki Ebisuya

    (RIKEN Center for Biosystems Dynamics Research (RIKEN BDR)
    European Molecular Biology Laboratory (EMBL) Barcelona)

  • Junya Toguchida

    (Kyoto University
    Kyoto University)

  • Cantas Alev

    (Kyoto University
    Kyoto University)

Abstract

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation1. Despite recent advances in in vitro induction of major mesodermal lineages and cell types2,3, experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR–Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.

Suggested Citation

  • Mitsuhiro Matsuda & Yoshihiro Yamanaka & Maya Uemura & Mitsujiro Osawa & Megumu K. Saito & Ayako Nagahashi & Megumi Nishio & Long Guo & Shiro Ikegawa & Satoko Sakurai & Shunsuke Kihara & Thomas L. Mau, 2020. "Recapitulating the human segmentation clock with pluripotent stem cells," Nature, Nature, vol. 580(7801), pages 124-129, April.
  • Handle: RePEc:nat:nature:v:580:y:2020:i:7801:d:10.1038_s41586-020-2144-9
    DOI: 10.1038/s41586-020-2144-9
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    Cited by:

    1. Ece Özelçi & Erik Mailand & Matthias Rüegg & Andrew C. Oates & Mahmut Selman Sakar, 2022. "Deconstructing body axis morphogenesis in zebrafish embryos using robot-assisted tissue micromanipulation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Marina Sanaki-Matsumiya & Mitsuhiro Matsuda & Nicola Gritti & Fumio Nakaki & James Sharpe & Vikas Trivedi & Miki Ebisuya, 2022. "Periodic formation of epithelial somites from human pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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