Reconstituting human somitogenesis in vitro
Reconstituting human somitogenesis in vitro
复制标题
体外重建人类体节发生
DOI：
10.1038/s41586-022-05649-2
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发表时间：
2022
期刊：
影响因子：
64.8
通讯作者：
Alev
中科院分区：
文献类型：
--
作者：
Yamanaka Yoshihiro;Hamidi Sofiane;Yoshioka-Kobayashi Kumiko;Munira Sirajam;Sunadome Kazunori;Zhang Yi;Kurokawa Yuzuru;Ericsson Rolf;Mieda Ai;Thompson Jamie L.;Kerwin Janet;Lisgo Steven;Yamamoto Takuya;Moris Naomi;Martinez-Arias Alfonso;Tsujimura Taro;Alev
脊椎动物的分段身体计划是在体节发生过程中建立的，这是一个在模式生物中得到充分研究的过程;然而，由于伦理和技术限制，人类这一过程的细节在很大程度上仍然未知。尽管最近的进展与多能干细胞为基础的方法，-，模型，强大的概括人类体节发生在空间和时间仍然很少。在这里，我们介绍了一个多能干细胞衍生的中胚层为基础的3D模型的人类分割和体节发生，我们称之为“axioloid”，准确地捕捉到的振荡动力学的分割时钟和连续体节形成的形态和分子特征在体外。Axioloids显示出形成节的适当喙尾模式以及强大的前后FGF-WNT信号梯度和视黄酸信号成分。我们确定了一个意想不到的关键作用，视黄酸信号在稳定的形成部分，表明不同的，但也协同效应的视黄酸和细胞外基质的体节的形成和上皮化。比较分析表明，axioloids的人类胚胎，进一步验证了存在一个Hox代码axioloids的显着相似性。最后，我们证明了axioloids的效用，研究人类先天性脊柱疾病的发病机制，诱导多能干细胞与突变HES 7和MESP 2。我们的研究结果表明，axioloids代表了一个很有前途的平台，轴向发展和疾病的研究在人类。
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 approaches, , , –, 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 inHES7andMESP2. Our results indicate that axioloids represent a promising platform for the study of axial development and disease in humans.