Forebrain neural progenitors effectively integrate into host brain circuits and improve neural function after ischemic stroke

Abstract

Abstract Human neural progenitor cell transplantation shows great potential in stroke treatment by replacing lost cortical neurons and repairing damaged brain circuits. However, the commonly utilized human neural progenitors fail to yield a substantial proportion of diverse cortical neurons and require an extended period to achieve synaptic integration, thereby diminishing the optimal benefits of cell transplantation for stroke. Here, we generated forkhead box G1 (FOXG1)-positive forebrain progenitors from human inducible pluripotent stem cells, which can differentiate into various cortical neurons including upper- and deep-layer excitatory and inhibitory neurons, achieving early functional maturation simultaneously in vitro. Furthermore, these FOXG1 forebrain progenitor cells achieved robust cortical neuronal differentiation, rapid functional maturation and efficient synaptic integration after transplantation into the sensory cortex of stroke-injured adult rats. Notably, we have successfully utilized the non-invasive 18F-SynVesT-1 PET imaging technique to assess alterations in synapse count before and after transplantation therapy of FOXG1 progenitors in vivo for the first time. Moreover, the transplanted FOXG1 progenitors improved fine motor behavior and prevented the onset of chronic post-stroke seizures. These findings provide systematic and compelling evidence for the suitability of these FOXG1 progenitors for neuronal replacement in ischemic cortical stroke.