Generation of Prefrontal Cortex Neurons from Human Pluripotent Stem Cells Under Chemically Defined Conditions

Human pluripotent stem cells (hPSCs) have the potential to differentiate into all human somatic cell types allowing for an experimental platform to access otherwise inaccessible tissues through directed differentiation protocols. Access to tissue is especially critical for neurobiology where functional human tissue is rare. The prefrontal cortex is an evolutionarily expanded addition to the cerebral cortex, associated with higher order cognitive function. Here, we present a method to generate neural progenitors and post-mitotic neurons with a prefrontal cortical identity through the directed differentiation of hPSCs under defined conditions. Neural induction is achieved by inhibiting TGF beta and BMP signaling (termed dual-SMAD inhibition) and neural progenitors are subsequently patterned toward the prefrontal cortex lineage using recombinant FGF8. Cells generated using this protocol open possibilities to study the unique developmental and synaptic properties of the prefrontal cortex, as well as to understand its selective vulnerability in a number of human brain disorders.