Abstract:

Recent efforts to reconstruct complex developmental processes in vitro from stem cells open up exciting new opportunities for studying the biological principles, which govern the emergence of form and function during embryonic development in humans and other non-model organisms. Early embryonic developmental events including somitogenesis, during which the metameric body plan of vertebrates is laid out, have been extensively studied using model organisms such as mouse or chick but remain largely elusive and poorly understood when it comes to human and other primates. Using induced pluripotent stem cell (iPSC)-derived presomitic mesoderm (PSM), we previously succeeded to quantify oscillatory activity of the segmentation clock, a molecular oscillator believed to control segmentation process (Matsuda, Yamanaka et al., Nature 2020; Matsuda et al., Science 2020). Interestingly, these in vitro models of the segmentation clock did not show any sign of segmentation or somitogenesis despite the presence of oscillatory activity of clock genes such as HES7. Extending on these earlier findings we then asked whether we could recapitulate not only the clock but also the actual process of segmentation and epithelial somite formation in vitro. Utilizing again pluripotent stem cells as starting material we succeeded to establish a 3D in vitro model of human somitogenesis, which exhibited periodic formation of properly patterned epithelial somites in synchrony with the segmentation clock (Yamanaka, Hamidi et al., Nature 2023). Our selforganizing ‘axioloids’ reconstituted various morphological and molecular features of the emerging human embryonic axis and could be also used to study the pathogenesis of human congenital diseases of the spine. Currently, we are continuing to improve and utilize axioloids and other in vitro models of embryonic development to increase our still limited understanding of development and disease in human and other primates.

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[2] Matsuda M, Yamanaka Y, Uemura M, Osawa M, Saito K. M, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen LT, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C*. Recapitulating the human segmentation clock with pluripotent stem cells. Nature. 2020 Apr 1;580(7801):124-129. DOI:10.1038/s41586-020-2144-9.

[3] Matsuda M, Hayashi H, Garcia-Ojalvo J, Yoshioka-Kobayashi K, Kageyama R, Yamanaka Y, Ikeya M, Toguchida J, Alev C, Ebisuya M. Species-specific oscillation periods of human and mouse segmentation clocks are due to cell autonomous differences in biochemical reaction parameters. Science. 2020 Sep 18;369(6510):1450-1455. DOI:10.1126/science.aba7668.