生物
细胞生物学
血脑屏障
维甲酸
串扰
平衡
胚胎干细胞
维甲酸
信号转导
神经科学
中枢神经系统
生物化学
基因
光学
物理
作者
Dor Zlotnik,Tatiana Rabinski,Aviv Halfon,Shira Anzi,Inbar Plaschkes,Hadar Benyamini,Yuval Nevo,Orly Yahalom Gershoni,Benyamin Rosental,Eli Hershkovitz,Ayal Ben‐Zvi,Gad D. Vatine
标识
DOI:10.1016/j.stemcr.2022.07.010
摘要
Summary
The blood-brain barrier (BBB) selectively regulates the entry of molecules into the central nervous system (CNS). A crosstalk between brain microvascular endothelial cells (BMECs) and resident CNS cells promotes the acquisition of functional tight junctions (TJs). Retinoic acid (RA), a key signaling molecule during embryonic development, is used to enhance in vitro BBB models' functional barrier properties. However, its physiological relevance and affected pathways are not fully understood. P450 oxidoreductase (POR) regulates the enzymatic activity of microsomal cytochromes. POR-deficient (PORD) patients display impaired steroid homeostasis and cognitive disabilities. Here, we used both patient-specific POR-deficient and CRISPR-Cas9-mediated POR-depleted induced pluripotent stem cell (iPSC)-derived BMECs (iBMECs) to study the role of POR in the acquisition of functional barrier properties. We demonstrate that POR regulates cellular RA homeostasis and that POR deficiency leads to the accumulation of RA within iBMECs, resulting in the impaired acquisition of TJs and, consequently, to dysfunctional development of barrier properties.
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