Department of Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
Systems Biology Research Center, School of Bioscience, University of Skövde, Skövde, Sweden.
Stem Cells. 2018 Dec;36(12):1816-1827. doi: 10.1002/stem.2908. Epub 2018 Nov 5.
Cell-based models of the blood-brain barrier (BBB) are important for increasing the knowledge of BBB formation, degradation and brain exposure of drug substances. Human models are preferred over animal models because of interspecies differences in BBB structure and function. However, access to human primary BBB tissue is limited and has shown degeneration of BBB functions in vitro. Human induced pluripotent stem cells (iPSCs) can be used to generate relevant cell types to model the BBB with human tissue. We generated a human iPSC-derived model of the BBB that includes endothelial cells in coculture with pericytes, astrocytes and neurons. Evaluation of barrier properties showed that the endothelial cells in our coculture model have high transendothelial electrical resistance, functional efflux and ability to discriminate between CNS permeable and non-permeable substances. Whole genome expression profiling revealed transcriptional changes that occur in coculture, including upregulation of tight junction proteins, such as claudins and neurotransmitter transporters. Pathway analysis implicated changes in the WNT, TNF, and PI3K-Akt pathways upon coculture. Our data suggest that coculture of iPSC-derived endothelial cells promotes barrier formation on a functional and transcriptional level. The information about gene expression changes in coculture can be used to further improve iPSC-derived BBB models through selective pathway manipulation. Stem Cells 2018;36:1816-12.
基于细胞的血脑屏障 (BBB) 模型对于增加对 BBB 形成、降解和药物物质向脑内暴露的了解非常重要。由于 BBB 结构和功能在物种间存在差异，因此人类模型优于动物模型。然而，获得人类原发性 BBB 组织是有限的，并且已经显示出 BBB 功能在体外退化。人类诱导多能干细胞 (iPSC) 可用于生成相关细胞类型，以具有人类组织的 BBB 进行建模。我们生成了一种包含内皮细胞与周细胞、星形胶质细胞和神经元共培养的人类 iPSC 衍生的 BBB 模型。对屏障特性的评估表明，我们的共培养模型中的内皮细胞具有高跨内皮电阻、功能性外排作用以及区分中枢神经系统可渗透和不可渗透物质的能力。全基因组表达谱分析显示，共培养过程中会发生转录变化，包括紧密连接蛋白（如 Claudin 和神经递质转运蛋白）的上调。通路分析表明，共培养后 WNT、TNF 和 PI3K-Akt 通路发生变化。我们的数据表明，iPSC 衍生的内皮细胞共培养可在功能和转录水平上促进屏障形成。共培养中基因表达变化的信息可用于通过选择性通路操作进一步改进 iPSC 衍生的 BBB 模型。干细胞 2018;36:1816-12。
