Self-organized morphogenesis of a stem cell-derived human neural tube

Eyal Karzbrun ¹ Aimal H. Khankhel ² Heitor C. Megale ³ Stella M. K. Glasauer ⁴ Yofiel Wyle ⁵ George Britton ⁶ Aryeh Warmflash ⁶ Kenneth S. Kosik ⁴ Eric D. Siggia ⁷ Boris I. Shraiman ³ Sebastian J. Streichan ³

¹Molecular Genetics, Weizmann Institute of Science, Israel
²Biomolecular Science and Engineering, University of California, USA
³Physics, University of California, Santa Barbara, USA
⁴Neuroscience Research Institute, University of California, Santa Barbara
⁵Department of Molecular, Cellular, Developmental Biology, University of California, Santa Barbara, USA
⁶Department of Bioengineering, Rice University, USA
⁷Center for Studies in Physics and Biology, The Rockefeller University, USA

Understanding human organ formation is a scientific challenge at the interface of developmental biology, soft-matter physics, and stem-cell research. However, current 3D human stem-cell models use scaffold-free platforms, which develop unreproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate and study dorgan formation. Here, we present a chip-based culture system that enables the self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes [1]. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction, the neural ectoderm folds into a millimeter-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity and anatomically resembles the developing human neural tube. We find that the neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms that drive folding: 1) apical contraction of neural ectoderm, and 2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using small molecules leads to neural tube defects. Finally, we develop a mechanical model which captures neural-tube morphology under all experimental conditions, further highlighting the role of tissue mechanics in organ morphogenesis. Our approach provides a new path for studying human organ morphogenesis in health and disease.

[1] Human neural tube morphogenesis in vitro by geometric constraints. E. Karzbrun, A. H. Khankhel, H. Megale, S. M. K. Glasauer, Y. Wyle, G. Britton, A. Warmflash, K. S. Kosik, E. D. Siggia, B. I. Shraiman, S. J. Streichan. Nature 599, 268–272 (2021).