Human pluripotent stem cell-derived neuroepithelial cells develop into an organizer for optic tectum formation in the...

Human brain development critically depends on the formation of secondary organizers, which determine specification of neural territories along the antero-posterior axis. Studies on human secondary organizers have proven to be difficult due to technical limitations and ethical concerns. Here, using interspecies transplantations we demonstrate that neuroepithelial cells (NECs) derived from human pluripotent stem cells (hPSCs) acquire properties of the isthmic organizer (IsO) when transplanted into the HH11 chicken anterior diencephalon, driving formation of a fully laminated optic tectum. hPSCs-derived NECs initially do not express the whole range of characteristic IsO molecules, but develop these features after transplantation and interaction within host tissue. We show that engineered human NECs act as dominant IsOs, overriding local signals in the chicken diencephalon to form a mesencephalic architecture, the optic tectum. The generation of IsOs from hPSCs offers new opportunities to study the pathogenesis of brain defects caused by malfunctions of the IsO.