Motor neurons project axons from the hindbrain and spinal cord to muscle, where they induce myofibre contractions through neurotransmitter release at neuromuscular junctions. Studies of neuromuscular junction formation and homeostasis have been largely confined to in vivo models. In this study, three powerful tools have been merged—pluripotent stem cells, optogenetics, and microfabrication—and an open microdevice is designed in which motor axons grow from a neural compartment containing embryonic stem cell‐derived motor neurons and astrocytes through microchannels to form functional neuromuscular junctions with contractile myofibres in a separate compartment. Optogenetic entrainment of motor neurons in this reductionist neuromuscular circuit enhances neuromuscular junction formation more than twofold, mirroring the activity‐dependence of synapse development in vivo. An established motor neuron disease model is incorporated into the system and it is found that coculture of motor neurons with SOD1G93A astrocytes results in denervation of the central compartment and diminishes myofibre contractions, a phenotype which is rescued by the receptor interacting serine/threonine kinase 1 inhibitor necrostatin. This coculture system replicates key aspects of nerve–muscle connectivity in vivo and represents a rapid and scalable alternative to animal models of neuromuscular function and disease.

The de novo formation of secretory lumens plays an important role during organogenesis. It involves the establishment of a cellular apical pole and the elongation of luminal cavities. The molecular parameters controlling cell polarization have been heavily scrutinized. In particular, signalling from the extracellular matrix (ECM) proved essential to the proper localization of the apical pole by directed protein transport. However, little is known about the regulation of the shape and the directional development of lumen into tubes. We demonstrate that the spatial scaffolding of cells by ECM can control tube shapes and can direct their elongation. We developed a minimal organ approach comprising of hepatocyte doublets cultured in artificial microniches to precisely control the spatial organization of cellular adhesions in three dimensions. This approach revealed a mechanism by which the spatial repartition of integrin-based adhesion can elicit an anisotropic intercellular mechanical stress guiding the osmotically driven elongation of lumens in the direction of minimal tension. This mechanical guidance accounts for the different morphologies of lumen in various microenvironmental conditions.