Long Term Maturation of Human Cortical Organoids Matches Key Early Postnatal Transitions

Human stem cell-derived models provide the promise of accelerating our understanding of brain disorders. But, not knowing whether they possess the ability to mature beyond late mid-fetal stages potentially limits their utility. So, we leveraged a directed differentiation protocol to comprehensively assess maturation in vitro. Based on genome-wide analysis of the epigenetic clock, transcriptomics, as well as RNA-editing, we observe that 3D human cortical organoids reach postnatal stages between 250–300 days, a timeline paralleling in vivo development. We demonstrate the presence of several known developmental milestones, including switches in the histone deacetylase complex and NMDA receptor subunits, which we confirm at the protein and physiological levels. These results suggest that important components of an intrinsic in vivo developmental program persist in vitro. We further map neurodevelopmental and neurodegenerative disease risk genes onto in vitro gene expression trajectories to provide a resource and webtool (GECO) to guide disease modeling.