A reproducible human stem cell system reveals neural tube morphogenesis

Neural tube folding is one of the earliest morphogenetic events in the human embryo, with defects affecting 1:1000 pregnancies a year. Years of studies in animal models, revealed species dependent mechanisms for neural tube formation, yet the origin of forces which drives tissue folding remains under debate. Recent advances in 3D stem-cell cultures [Organoids] raised a promise to study developmental biology in a human genetic context. However, the large variability and lack of predictability in organoid systems, severely limits their potential applications. Here, we developed a highly reproducible three-dimensional human stem-cell culture, essentially solving the organoid variability problem. Remarkably, our system exhibits folding morphogenesis which is highly similar to neural tube formation. We perform a quantitative morphometric analysis, and discover that folding morphogenesis is driven by a combination of cell contractility and active tissue wetting. These findings have strong implications to our understanding of neural tube development in humans. In the future, our platform can be expanded to study morphogenesis of additional organs, from the lung to the heart.