Controlling organoid symmetry breaking uncovers an excitable system underlying human axial elongation

• Published in: Cell Vol. 186; no. 3; pp. 497 - 512.e23
• Main Authors: Anand, Giridhar M., Megale, Heitor C., Murphy, Sean H., Weis, Theresa, Lin, Zuwan, He, Yichun, Wang, Xiao, Liu, Jia, Ramanathan, Sharad
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.02.2023
• Subjects: axial elongation; bioengineering; Body Patterning; Embryo, Mammalian; human stem cell models; Humans; Mesoderm; Organoids; reproducible; statistical inference; Wnt Signaling Pathway; statistical inference; axial elongation; reproducible; human stem cell models; bioengineering
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.12.043

The human embryo breaks symmetry to form the anterior-posterior axis of the body. As the embryo elongates along this axis, progenitors in the tail bud give rise to tissues that generate spinal cord, skeleton, and musculature. This raises the question of how the embryo achieves axial elongation and patterning. While ethics necessitate in vitro studies, the variability of organoid systems has hindered mechanistic insights. Here, we developed a bioengineering and machine learning framework that optimizes organoid symmetry breaking by tuning their spatial coupling. This framework enabled reproducible generation of axially elongating organoids, each possessing a tail bud and neural tube. We discovered that an excitable system composed of WNT/FGF signaling drives elongation by inducing a neuromesodermal progenitor-like signaling center. We discovered that instabilities in the excitable system are suppressed by secreted WNT inhibitors. Absence of these inhibitors led to ectopic tail buds and branches. Our results identify mechanisms governing stable human axial elongation. [Display omitted] •Spatially coupled human organoids achieve robust A-P symmetry breaking•Organoids elongate axially and generate cell types of the posterior neural tube•Elongation is sustained by WNT/FGF feedback through an NMP-like signaling center•Elongation is stabilized by secreted inhibitors of WNT signaling A machine learning-driven bioengineering approach generates a robust stem cell model of human axial elongation that uncovers molecular mechanisms underlying self-sustained and stable elongation.