Modeling Human Axial Patterning and Segmentation

Abstract

During embryonic development, the body plan is established through the precise coordination of cell signaling, fate specification, and morphogenesis across space and time. In vertebrates, this is exemplified by somitogenesis—the sequential formation of somites during axial development—which segments the body and relies on tightly regulated differentiation and morphogenesis. While the molecular players and signaling mechanisms of somitogenesis vary across model organisms, our understanding of human axial morphogenesis has been limited by the inaccessibility of early human embryos. Here, we overcome these challenges by generating axially elongating organoids through the induction of anteroposterior symmetry breaking in spatially coupled epithelial cysts derived from human pluripotent stem cells. These organoids reproducibly recapitulate the formation of a neural tube flanked by presomitic mesoderm that is sequentially and periodically segmented into anteroposteriorly polarized somites. Using a combination of chemical and genetic perturbations, single-cell transcriptomics, and live fluorescent microscopy, we investigate the principles linking the spatiotemporal dynamics of signaling, patterning, and morphogenesis during human axial development. By generating and perturbing organoids that robustly recapitulate the architecture of multiple axial tissues found in human embryos, this work provides a platform to dissect the mechanisms driving human development.