Rationally Design and Acoustically Assemble Human Cerebral Cortex-like Microtissues from hiPSC-derived Neural Progenitors and Neurons.

Development of human biologically relevant and clinically relevant cerebral cortex models is demanded by mechanistic studies of human cerebral cortex-associated neurological diseases and discovery of preclinical neurological drug candidates. Here, we demonstrated rational design of human sourced brain-like cortical tissue models by reverse engineering and bionic design. To implement this design, we employed acoustic assembly technique to assemble hiPSC-derived neural progenitors and neurons separately in a label-free and contact-free manner followed by subsequent neural differentiation and culture. The generated microtissues encapsulated neuronal microanatomy of human cerebral-cortex tissue that contained six-layered neuronal architecture, 400-micrometer interlayer distance, synaptic connections between interlayers, and neuroelectrophysiological transmission. Furthermore, we infected these microtissues with HSV-1 virus and determined the HSV-induced pathogenesis associated with Alzheimer's disease, including neuron loss and the expression of Aβ. Overall, we provided a high-fidelity human-relevant in vitro histotypic models for cerebral cortex, and these models will facilitate wide applications in probing the mechanisms of neurodegenerative diseases and screening the candidates of neuroprotective agents. This article is protected by copyright. All rights reserved.