Pyramidal Neurons Derived from Human Pluripotent Stem Cells Integrate Efficiently into Mouse Brain Circuits In Vivo

The generation of in vitro and in vivo models to study human cortical development is essential to address the molecular and cellular mechanisms involved in brain evolution as well as to elucidate major pathways affected in developmental and degenerative cortical diseases. Here we found that human embryonic (ESC) and induced pluripotent (iPSC) stem cells, cultured without added morphogens, recapitulate corticogenesis in vitro leading to the sequential generation of functional pyramidal neurons of all six layers identities. Following transplantation into the mouse neonatal brain, human ESC-derived cortical neurons integrated robustly and established specific axonal projections corresponding to native cortical neurons of diverse cortical layers and areas. Neuronal differentiation and connectivity complexified progressively over several months in vivo, culminating with the development of elaborate dendritic patterns, the presence of dendritic spines, and the establishment of reciprocal synapses with the host in a time dependent fashion highly reminiscent of the human species. Our data demonstrate that human cortical neurons generated in vitro from ESC/iPSC can develop complex hodological properties characteristic of the cerebral cortex in vivo, thereby offering unprecedented opportunities for the modelling of human cortex diseases, and brain repair.