Coupled organoids reveal that signaling gradients drive traveling segmentation clock waves during human axial morphogenesis

Summary Axial development of mammals is a dynamic process involving several coordinated morphogenetic events including axial elongation, somitogenesis, and neural tube formation. How different signals control the dynamics of human axial morphogenesis remains largely unknown. By inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells, we were able to generate hundreds of axially elongating organoids. Each organoid was composed of a neural tube flanked by presomitic mesoderm that was 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 key aspects of somitogenesis. Through timed perturbations of organoids, we demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis, and that the segmentation clock waves are driven by FGF signaling gradients. By generating and perturbing organoids that robustly recapitulate the architecture and dynamics of multiple axial tissues in human embryos, this work offers a means to dissect complex mechanisms underlying human embryogenesis.