Human cortical progenitors transplanted into the ischemic adult mouse motor cortex mature into distinct neuronal subtypes that establish targeted projections to appropriate cortical and subcortical regions including the corticospinal tract through subtype-specific transcriptional codes comprising unique combinations of axon guidance and synapse assembly genes, which can be identified by machine learning to predict successful circuit integration and functional motor recovery.

Neural transplantation holds the potential to repair damaged neural circuits in neurological diseases. However, it remains unknown how the grafted neurons project axons to and make functional connections with the appropriate targets to repair the damaged circuit at the adult stage. Here we report that human cortical progenitors, transplanted into the ischemic mouse motor cortex, matured and integrated into cortical and subcortical neural circuits including the corticospinal tract. Neuronal tracing combined with single-nuclei RNA sequencing revealed the close relationship between the transcription profiles of a cortical neuronal subtype, especially those of axon guidance and synapse assembly, with the specific target projection and synapse organization. Machine learning-based regression further identified the transcriptional codes for the targeted projection and circuit integration to reconstruct the damaged circuits. Our finding opens a promising strategy for treating neurological diseases through promoting regeneration and neural transplantation.

Highlights

Human ESC-derived cortical neurons reconstitute the ischemic motor cortex Functionally repaired corticospinal tract restores animal behaviors

Transplanted cortical neurons exhibit subtype-specific projection and integration Unique transcriptional coding for axonal navigation in the mature CNS