In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells.
Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell-derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-α, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs.
Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
Yasuhiro
Y
Kokubu
Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan.
Tomoko
T
Yamaguchi
Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, 7-6-8, Saito-Asagi, Ibaraki, Osaka, 567-0085, Japan. Electronic address: kawabata@nibiohn.go.jp.
Kenji
K
Kawabata
D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000494:pharmacology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008954:Models, Biological; D010100:Oxygen / Q000494:pharmacology*; D010539:Permeability; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D005947:Glucose; D010100:Oxygen
BBB; OGD; OGD/R; TEER; TNF-α; iPS cell