体细胞发生
体节
近轴中胚层
生物
维甲酸
Wnt信号通路
Hox基因
诱导多能干细胞
中胚层
细胞生物学
遗传学
胚胎干细胞
胚胎
信号转导
细胞培养
基因
胚胎发生
转录因子
作者
Yoshihiro Yamanaka,Sofiane Hamidi,Kumiko Yoshioka-Kobayashi,Sirajam Munira,Kazunori Sunadome,Yi Zhang,Yuzuru Kurokawa,Rolf Ericsson,Ai Mieda,Jamie Thompson,Janet Kerwin,Steven Lisgo,Takuya Yamamoto,Naomi Moris,Alfonso Martínez-Arias,Taro Tsujimura,Cantas Alev
出处
期刊:Nature
[Springer Nature]
日期:2022-12-21
卷期号:614 (7948): 509-520
被引量:60
标识
DOI:10.1038/s41586-022-05649-2
摘要
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. A 3D model of human segmentation and somitogenesis derived from induced pluripotent stem cells captures the oscillatory dynamics of the segmentation clock as well as morphological and molecular features of the developing embryonic axis and tail.
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