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Neural tube morphogenesis in synthetic 3D microenvironments

Significance In vitro organoids have become widely used model systems in basic research and for therapeutic applications due to their ability to recapitulate key elements of in vivo form and function. However, their full potential remains unfulfilled as a result of the poorly defined matrices in which they are grown. Here, we use modular synthetic 3D matrices to show that early neural morphogenesis can be precisely controlled by the extracellular microenvironment. Our approach is broadly applicable to gain a broader understanding of the multifactorial 3D cell–matrix interactions that coordinate multicellular growth and differentiation, and opens up avenues to discover and dissect the unique microenvironments that control morphogenesis in various organoid systems. Three-dimensional organoid constructs serve as increasingly widespread in vitro models for development and disease modeling. Current approaches to recreate morphogenetic processes in vitro rely on poorly controllable and ill-defined matrices, thereby largely overlooking the contribution of biochemical and biophysical extracellular matrix (ECM) factors in promoting multicellular growth and reorganization. Here, we show how defined synthetic matrices can be used to explore the role of the ECM in the development of complex 3D neuroepithelial cysts that recapitulate key steps in early neurogenesis. We demonstrate how key ECM parameters are involved in specifying cytoskeleton-mediated symmetry-breaking events that ultimately lead to neural tube-like patterning along the dorsal–ventral (DV) axis. Such synthetic materials serve as valuable tools for studying the discrete action of extrinsic factors in organogenesis, and allow for the discovery of relationships between cytoskeletal mechanobiology and morphogenesis.