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Somatic PDGFRB activating variants promote smooth muscle cell phenotype modulation in intracranial fusiform aneurysm.
Hao, Li; Ya, Xiaolong; Wu, Jiaye; Tao, Chuming; Ma, Ruochen; Zheng, Zhiyao; Mou, Siqi; Ling, Yiming; Yang, Yingxi; Wang, Jiguang; Zhang, Yan; Lin, Qing; Zhao, Jizong.
Afiliación
  • Hao L; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Ya X; China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China.
  • Wu J; Joint Laboratory of School of Pharmacy, Capital Medical University and National Clinical Research Center for Nervous System Diseases, Beijing, China.
  • Tao C; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Ma R; China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China.
  • Zheng Z; Joint Laboratory of School of Pharmacy, Capital Medical University and National Clinical Research Center for Nervous System Diseases, Beijing, China.
  • Mou S; Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, 510006, China.
  • Ling Y; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
  • Yang Y; China National Clinical Research Center for Neurological Diseases, Beijing, 100070, China.
  • Wang J; HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China.
  • Zhang Y; Department of Chemical and Biological Engineering, Division of Life Science, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
  • Lin Q; Hong Kong Center for Neurodegenerative Diseases, InnoHK, HKSAR, China.
  • Zhao J; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
J Biomed Sci ; 31(1): 51, 2024 May 13.
Article en En | MEDLINE | ID: mdl-38741091
ABSTRACT

BACKGROUND:

The fusiform aneurysm is a nonsaccular dilatation affecting the entire vessel wall over a short distance. Although PDGFRB somatic variants have been identified in fusiform intracranial aneurysms, the molecular and cellular mechanisms driving fusiform intracranial aneurysms due to PDGFRB somatic variants remain poorly understood.

METHODS:

In this study, single-cell sequencing and immunofluorescence were employed to investigate the phenotypic changes in smooth muscle cells within fusiform intracranial aneurysms. Whole-exome sequencing revealed the presence of PDGFRB gene mutations in fusiform intracranial aneurysms. Subsequent immunoprecipitation experiments further explored the functional alterations of these mutated PDGFRB proteins. For the common c.1684 mutation site of PDGFRß, we established mutant smooth muscle cell lines and zebrafish models. These models allowed us to simulate the effects of PDGFRB mutations. We explored the major downstream cellular pathways affected by PDGFRBY562D mutations and evaluated the potential therapeutic effects of Ruxolitinib.

RESULTS:

Single-cell sequencing of two fusiform intracranial aneurysms sample revealed downregulated smooth muscle cell markers and overexpression of inflammation-related markers in vascular smooth muscle cells, which was validated by immunofluorescence staining, indicating smooth muscle cell phenotype modulation is involved in fusiform aneurysm. Whole-exome sequencing was performed on seven intracranial aneurysms (six fusiform and one saccular) and PDGFRB somatic mutations were detected in four fusiform aneurysms. Laser microdissection and Sanger sequencing results indicated that the PDGFRB mutations were present in smooth muscle layer. For the c.1684 (chr5 149505131) site mutation reported many times, further cell experiments showed that PDGFRBY562D mutations promoted inflammatory-related vascular smooth muscle cell phenotype and JAK-STAT pathway played a crucial role in the process. Notably, transfection of PDGFRBY562D in zebrafish embryos resulted in cerebral vascular anomalies. Ruxolitinib, the JAK inhibitor, could reversed the smooth muscle cells phenotype modulation in vitro and inhibit the vascular anomalies in zebrafish induced by PDGFRB mutation.

CONCLUSION:

Our findings suggested that PDGFRB somatic variants played a role in regulating smooth muscle cells phenotype modulation in fusiform aneurysms and offered a potential therapeutic option for fusiform aneurysms.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aneurisma Intracraneal / Receptor beta de Factor de Crecimiento Derivado de Plaquetas / Miocitos del Músculo Liso Límite: Animals / Female / Humans / Male Idioma: En Revista: J Biomed Sci Asunto de la revista: MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Aneurisma Intracraneal / Receptor beta de Factor de Crecimiento Derivado de Plaquetas / Miocitos del Músculo Liso Límite: Animals / Female / Humans / Male Idioma: En Revista: J Biomed Sci Asunto de la revista: MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido