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CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using...

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Detalles Bibliográficos
Autores principales: Wang, Ping, Liu, Zunpeng, Zhang, Xiaoqian, Li, Jingyi, Sun, Liang, Ju, Zhenyu, Li, Jian, Chan, Piu, Liu, Guang-Hui, Zhang, Weiqi, Song, Moshi, Qu, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Higher Education Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208479/
https://www.ncbi.nlm.nih.gov/pubmed/29968158
http://dx.doi.org/10.1007/s13238-018-0560-5
Descripción
Sumario:Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells (hESCs) and differentiated them into various vascular cell derivatives to study how NF-κB modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulating inflammation, survival, vasculogenesis, cell differentiation and extracellular matrix organization in a cell type-specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modulated vascular inflammatory response upon tumor necrosis factor α (TNFα) stimulation. Lastly, further evaluation of gene expression patterns in IκBα knockout vascular cells demonstrated that IκBα acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/RelA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13238-018-0560-5) contains supplementary material, which is available to authorized users.