Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology

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<sup>+</sup> 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.

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Publication Details

Journal
Nature Communications
Published
2025-04-08
DOI
https://doi.org/10.1038/s41467-025-58535-6
Citations
6
Primary Topic
Platelet Disorders and Treatments
Type
article
Field-Weighted Citation Impact
10.62

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article

Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology

Maozhi Ren, Shaojie Ma, Xinyu Mei, Licheng Sun et al.
6 citations
Nature Communications
Platelet Disorders and Treatments
10.62
article

Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology

Maozhi Ren, Shaojie Ma, Xinyu Mei, Licheng Sun, Chuantao Fang, Jinsen Zhang, Yujia Lu, Jingjing Guo, Guoping Liu, Yi Liu, Xiaodan Zhang, Li Zhu, Lin Yang, Min Wang, Xin Gao, Dashi Qi, Yanfeng Tan, Jianbo Xiao, Fayong Zhang, Ruoxuan Zhao
article en
6 citations

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<sup>+</sup> 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.

Nature CommunicationsVol. 16(1)
Tongji University (CN), Shanghai Jiao Tong University (CN), Fudan University (CN), Shanghai Medical Information Center (CN), Center for Excellence in Brain Science and Intelligence Technology (CN), Shanghai Tenth People's Hospital (CN), Chinese Academy of Agricultural Sciences (CN), Obstetrics and Gynecology Hospital of Fudan University (CN), Children's Hospital of Fudan University (CN), Shanghai Children's Hospital (CN), Huashan Hospital (CN), Sichuan Academy of Agricultural Sciences (CN), University of Chinese Academy of Sciences (CN), Yangpu Hospital of Tongji University (CN), Universidade de Vigo (ES), Hainan Medical University (CN)
Natural Science Foundation of Shanghai, Shanghai Municipal Health Commission, National Natural Science Foundation of China
Zero hunger
Openalex Percentile: Top 2%
Platelet Disorders and Treatments
10.62
DOIOpen Access PDFOpenAlex
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