John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Cell. 2023 Feb 2;186(3):513-527.e19. doi: 10.1016/j.cell.2022.12.042. Epub 2023 Jan 18.
Axial development of mammals involves coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the signals controlling the dynamics of human axial morphogenesis, we generated axially elongating organoids by inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells. Each organoid was composed of a neural tube flanked by presomitic mesoderm sequentially segmented into somites. Periodic activation of the somite differentiation gene MESP2 coincided in space and time with anteriorly traveling segmentation clock waves in the presomitic mesoderm of the organoids, recapitulating critical aspects of somitogenesis. Timed perturbations demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis, and that FGF signaling gradients drive segmentation clock waves. By generating and perturbing organoids that robustly recapitulate the architecture of multiple axial tissues in human embryos, this work offers a means to dissect mechanisms underlying human embryogenesis.
哺乳动物的轴向发育涉及协调的形态发生事件，包括轴向伸长、体节发生和神经管形成。为了深入了解控制人类轴向形态发生动力学的信号，我们通过诱导源自人类多能干细胞的空间耦合上皮囊肿的前后对称性破坏，生成了轴向伸长的类器官。每个类器官由神经管和依次分段为体节的生骨节间充质组成。体节分化基因 MESP2 的周期性激活在空间和时间上与类器官中生骨节间充质中向前传播的分段时钟波一致，再现了体节发生的关键方面。定时干扰表明，FGF 和 WNT 信号在轴向伸长和体节发生中发挥不同的作用，并且 FGF 信号梯度驱动分段时钟波。通过生成和干扰类器官，这些类器官能够强有力地再现人类胚胎中多个轴向组织的结构，这项工作提供了一种剖析人类胚胎发生机制的方法。
