Reconstituting human somitogenesis in vitro

Yoshihiro Yamanaka, Sofiane Hamidi, Kumiko Yoshioka-Kobayashi, Sirajam Munira, Kazunori Sunadome, Yi Zhang, Yuzuru Kurokawa, Rolf Ericsson, Ai Mieda, Jamie L. Thompson, Janet Kerwin, Steven Lisgo, Takuya Yamamoto, Naomi Moris, Alfonso Martinez-Arias, Taro Tsujimura and Cantas Alev ()
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Yoshihiro Yamanaka: Kyoto University
Sofiane Hamidi: Kyoto University
Kumiko Yoshioka-Kobayashi: Kyoto University
Sirajam Munira: Kyoto University
Kazunori Sunadome: Kyoto University
Yi Zhang: Kyoto University
Yuzuru Kurokawa: Kyoto University
Rolf Ericsson: Kyoto University
Ai Mieda: Kyoto University
Jamie L. Thompson: The Francis Crick Institute
Janet Kerwin: Newcastle University
Steven Lisgo: Newcastle University
Takuya Yamamoto: Kyoto University
Naomi Moris: The Francis Crick Institute
Alfonso Martinez-Arias: Universitat Pompeu Fabra and ICREA
Taro Tsujimura: Kyoto University
Cantas Alev: Kyoto University

Nature, 2023, vol. 614, issue 7948, 509-520

Abstract: Abstract The segmented body plan of vertebrates is established during somitogenesis, a well-studied process in model organisms; however, the details of this process in humans remain largely unknown owing to ethical and technical limitations. Despite recent advances with pluripotent stem cell-based approaches1–5, models that robustly recapitulate human somitogenesis in both space and time remain scarce. Here we introduce a pluripotent stem cell-derived mesoderm-based 3D model of human segmentation and somitogenesis—which we termed ‘axioloid’—that captures accurately the oscillatory dynamics of the segmentation clock and the morphological and molecular characteristics of sequential somite formation in vitro. Axioloids show proper rostrocaudal patterning of forming segments and robust anterior–posterior FGF–WNT signalling gradients and retinoic acid signalling components. We identify an unexpected critical role of retinoic acid signalling in the stabilization of forming segments, indicating distinct, but also synergistic effects of retinoic acid and extracellular matrix on the formation and epithelialization of somites. Comparative analysis demonstrates marked similarities of axioloids to the human embryo, further validated by the presence of a Hox code in axioloids. Finally, we demonstrate the utility of axioloids for studying the pathogenesis of human congenital spine diseases using induced pluripotent stem cells with mutations in HES7 and MESP2. Our results indicate that axioloids represent a promising platform for the study of axial development and disease in humans.

Date: 2023
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DOI: 10.1038/s41586-022-05649-2

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