Human Stem Cell-Derived Neurons Repair Circuits and Restore Neural Function

Although cell transplantation can rescue motor defects in Parkinson’s disease (PD) models, whether and how grafts functionally repair damaged neural circuitry in the adult brain is not known. We transplanted hESC-derived midbrain dopamine (mDA) or cortical glutamate neurons into the substantia nigra or striatum of a mouse PD model and found extensive graft integration with host circuitry. Axonal pathfinding toward the dorsal striatum was determined by the identity of the grafted neurons, and anatomical presynaptic inputs were largely dependent on graft location, whereas inhibitory versus excitatory input was dictated by the identity of grafted neurons. hESC-derived mDA neurons display A9 characteristics and restore functionality of the reconstructed nigrostriatal circuit to mediate improvements in motor function. These results indicate similarity in cell-type-specific pre- and post-synaptic integration between transplant-reconstructed circuit and endogenous neural networks, highlighting the capacity of hPSC-derived neuron subtypes for specific circuit repair and functional restoration in the adult brain. [Display omitted] •Human ESC-derived mDA neurons exhibit A9-like DA neuron characteristics•Functional synaptic inputs depend on the grafted neuronal type but not graft site•Human mDA neurons repair the nigra-striatal circuit with precision•Functionally repaired nigra-striatal circuit restores animal behavior Xiong et al. found that genetically labeled hESC-derived midbrain dopamine (mDA) neurons, following transplantation into the brain of Parkinson’s disease mice, repair the nigra-striatal circuit anatomically and functionally. Furthermore, functional innervation into the graft depends on cell identity, highlighting the necessity of correct cell types for cell therapy.