Human cortical organoids from single iPSC‐derived neural rosettes for studying human cortical development and disorders

Abstract

Human cerebral cortex is the most complex brain structure implicated in many human‐specific behaviors and disorders. Genes important for the development and wiring of human cortex have often been found mutated in individuals with neurodevelopment disorders. Cerebral organoids generated from human embryonic and induced pluripotent stem cells have been used for modeling human‐specific aspects of cortical development; however, some variability‐ and maturation‐related issues prohibit the widespread use of these approach for disease modeling. We developed a new protocol for growing human cortical organoids from single stem cell‐derived neural rosettes and demonstrated that single‐rosette‐derived cortical organoids grow large in suspension culture, reaching 4–5 mm in diameter by 4 months, and consist of different types of properly organized neuronal cells, including cortical neural progenitors, deep and superficial cortical excitatory neurons, inhibitory neurons, and astrocytes. Using slice patch‐clamp electrophysiology, we show that many neurons in slices from single‐rosette‐derived cortical organoids fire repetitive action potentials, receive excitatory and inhibitory synaptic inputs, exhibit typical pyramidal‐like morphologies, and have dendritic spines. Our results indicate that single‐rosette‐derived cortical organoids can be used as a more robust experimental system for modeling human cortical development and disorders.Support or Funding InformationUtah Neuroscience Initiative Seed Grant, Whitehall Foundation, Brain Research Foundation, Brain and Behavior Research Foundation, NIMH, NINDSThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.