Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology
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 si...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58535-6 |
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| author | 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 Dashi Qi |
| author_facet | 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 Dashi Qi |
| author_sort | Chuantao Fang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-db491539c9a14d9f89b7b2d6594a3eb9 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-db491539c9a14d9f89b7b2d6594a3eb92025-08-20T03:10:10ZengNature PortfolioNature Communications2041-17232025-04-0116111110.1038/s41467-025-58535-6Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiologyChuantao Fang0Xiaodan Zhang1Lin Yang2Licheng Sun3Yujia Lu4Yi Liu5Jingjing Guo6Min Wang7Yanfeng Tan8Jinsen Zhang9Xin Gao10Li Zhu11Guoping Liu12Maozhi Ren13Jianbo Xiao14Fayong Zhang15Shaojie Ma16Rui Zhao17Xinyu Mei18Dashi Qi19Center for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji UniversityInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityCenter for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji UniversityCenter for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji UniversityUniversidade de Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Instituto de Agroecoloxía e Alimentación (IAA) – CITEXVICenter for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji UniversityInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityShanghai Universal Medical Imaging Diagnostic CenterInstitute of Translational Medicine, Shanghai Jiao Tong UniversityInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityInstitute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu National Agricultural Science and Technology CenterUniversidade de Vigo, Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Instituto de Agroecoloxía e Alimentación (IAA) – CITEXVIInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of SciencesInstitute of Pediatrics, Children’s Hospital of Fudan University, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Obstetrics and Gynecology Hospital of Fudan University and Department of Neurology, Huashan Hospital of Fudan University, Fudan UniversityCenter for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji UniversityCenter for Clinical Research and Translational Medicine, Yangpu Hospital, School of Medicine, Tongji UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58535-6 |
| spellingShingle | 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 Dashi Qi Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology Nature Communications |
| title | Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology |
| title_full | Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology |
| title_fullStr | Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology |
| title_full_unstemmed | Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology |
| title_short | Transcriptomic and morphologic vascular aberrations underlying FCDIIb etiology |
| title_sort | transcriptomic and morphologic vascular aberrations underlying fcdiib etiology |
| url | https://doi.org/10.1038/s41467-025-58535-6 |
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