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Cell stress in cortical organoids impairs molecular subtype specification (Organoids)
Aparna Bhaduri, Madeline G. Andrews, Walter Mancia Leon, Diane Jung, David Shin, Denise Allen, Dana Jung, Galina Schmunk, Maximilian Haeussler, Jahan Salma, Alex A. Pollen, Tomasz J. Nowakowski, Arnold R. Kriegstein.
Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex. However, the fdelity of organoid models remains unclear. Here we analyse the transcriptomes of individual primary human cortical cells from diferent developmental periods and cortical areas. We fnd that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specifcation of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specifcation. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.