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

Xiao He, Jiadong Chen, Yan Zhong, Peili Cen, Li Shen, Fei Huang, Jing Wang, Chentao Jin, Rui Zhou, Xiaohui Zhang, Anxin Wang, Jing Fan, Shuang Wu, Mengjiao Tu, Xiyi Qin, Xiaoyun Luo, Yu Zhou, Jieqiao Peng, Youyou Zhou, A. Cahid Civelek, Mei Tian () and Hong Zhang ()
Additional contact information
Xiao He: Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences
Jiadong Chen: Zhejiang University School of Medicine
Yan Zhong: The Second Affiliated Hospital of Zhejiang University School of Medicine
Peili Cen: The Second Affiliated Hospital of Zhejiang University School of Medicine
Li Shen: Zhejiang University
Fei Huang: Zhejiang University
Jing Wang: The Second Affiliated Hospital of Zhejiang University School of Medicine
Chentao Jin: The Second Affiliated Hospital of Zhejiang University School of Medicine
Rui Zhou: The Second Affiliated Hospital of Zhejiang University School of Medicine
Xiaohui Zhang: The Second Affiliated Hospital of Zhejiang University School of Medicine
Anxin Wang: Ltd.
Jing Fan: Ltd.
Shuang Wu: The Second Affiliated Hospital of Zhejiang University School of Medicine
Mengjiao Tu: The Second Affiliated Hospital of Zhejiang University School of Medicine
Xiyi Qin: The Second Affiliated Hospital of Zhejiang University School of Medicine
Xiaoyun Luo: The Second Affiliated Hospital of Zhejiang University School of Medicine
Yu Zhou: Zhejiang University School of Medicine
Jieqiao Peng: Zhejiang University School of Medicine
Youyou Zhou: The Second Affiliated Hospital of Zhejiang University School of Medicine
A. Cahid Civelek: Johns Hopkins Medicine
Mei Tian: The Second Affiliated Hospital of Zhejiang University School of Medicine
Hong Zhang: Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract Human cortical neural progenitor cell transplantation holds significant potential in cortical stroke treatment by replacing lost cortical neurons and repairing damaged brain circuits. However, commonly utilized human cortical neural progenitors are limited in yield a substantial proportion of diverse cortical neurons and require an extended period to achieve functional maturation and synaptic integration, thereby potentially diminishing the optimal therapeutic benefits of cell transplantation for cortical stroke. Here, we generated forkhead box G1 (FOXG1)-positive forebrain progenitors from human inducible pluripotent stem cells, which can differentiate into diverse and balanced cortical neurons including upper- and deep-layer excitatory and inhibitory neurons, achieving early functional maturation simultaneously in vitro. Furthermore, these FOXG1 forebrain progenitor cells demonstrate 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. Moreover, the transplanted FOXG1 progenitors improve sensory and motor function recovery following stroke. These findings provide systematic and compelling evidence for the suitability of these FOXG1 progenitors for neuronal replacement in ischemic cortical stroke.

Date: 2025
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DOI: 10.1038/s41467-025-60187-5

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