Transcriptional code for circuit integration in the injured brain by transplanted human neurons

Abstract

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.

Keywords: circuit integration code; corticospinal tract; human pluripotent stem cell-derived neuron; neural circuit integration; neural transplantation; neurological disorders; neuronal replacement; stroke.