Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology

Chuantao Fang, Xiaodan Zhang, Lin Yang, Licheng Sun, Yujia Lu, Yi Liu, Jingjing Guo, Min Wang, Yanfeng Tan, Jinsen Zhang, Xin Gao, Li Zhu, Guoping Liu, Maozhi Ren, Jianbo Xiao, Fayong Zhang, Shaojie Ma, Rui Zhao (), Xinyu Mei () and Dashi Qi ()
Additional contact information
Chuantao Fang: Tongji University
Xiaodan Zhang: Fudan University
Lin Yang: Fudan University
Licheng Sun: Tongji University
Yujia Lu: Tongji University
Yi Liu: Instituto de Agroecoloxía e Alimentación (IAA) – CITEXVI
Jingjing Guo: Tongji University
Min Wang: Fudan University
Yanfeng Tan: Fudan University
Jinsen Zhang: Fudan University
Xin Gao: Shanghai Universal Medical Imaging Diagnostic Center
Li Zhu: Shanghai Jiao Tong University
Guoping Liu: Fudan University
Maozhi Ren: Chengdu National Agricultural Science and Technology Center
Jianbo Xiao: Instituto de Agroecoloxía e Alimentación (IAA) – CITEXVI
Fayong Zhang: Fudan University
Shaojie Ma: Chinese Academy of Sciences
Rui Zhao: Fudan University
Xinyu Mei: Tongji University
Dashi Qi: Tongji University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Focal cortical dysplasia type II (FCDII) is a major cause of drug-resistant epilepsy, but genetic factors explain only some cases, suggesting other mechanisms. In this study, we conduct a molecular analysis of brain lesions and adjacent areas in FCDIIb patients. By analyzing over 217,506 single-nucleus transcriptional profiles from 15 individuals, we find significant changes in smooth muscle cells (SMCs) and astrocytes. We identify abnormal vascular malformations and a unique type of SMC that we call “Firework cells”, which migrate from blood vessels into the brain parenchyma and associate with VIM+ cells. These abnormalities create localized ischemic-hypoxic (I/H) microenvironments, as confirmed by clinical data, further impairing astrocyte function, activating the HIF-1α/mTOR/S6 pathway, and causing neuronal loss. Using zebrafish models, we demonstrate that vascular abnormalities resulting in I/H environments promote seizures. Our results highlight vascular malformations as a factor in FCDIIb pathogenesis, suggesting potential therapeutic avenues.

Date: 2025
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DOI: 10.1038/s41467-025-58535-6

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