Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.
Huntington's Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits.
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DOI：
10.1016/j.celrep.2017.04.021
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发表时间：
2017-05-16
期刊：
影响因子：
8.8
通讯作者：
Thompson LM
中科院分区：
文献类型：
--
作者：
Lim RG;Quan C;Reyes-Ortiz AM;Lutz SE;Kedaigle AJ;Gipson TA;Wu J;Vatine GD;Stocksdale J;Casale MS;Svendsen CN;Fraenkel E;Housman DE;Agalliu D;Thompson LM
脑微血管内皮细胞（BMEC）是血脑屏障（BBB）的重要组成部分，可保护大脑免受毒素和免疫细胞的侵害。虽然BBB功能障碍存在于神经系统疾病中，包括亨廷顿病（HD），但尚不清楚BMEC本身是否在功能上受损以促进BBB功能障碍。此外，由于小鼠模型和死后组织的局限性，BBB功能障碍的潜在机制仍然难以捉摸，以确定原发性缺陷。我们对来自HD患者或未受影响的对照的人诱导多能干细胞（iPSC）衍生的BMEC（iBMEC）进行了转录组和功能分析。我们证明了HD iBMEC在血管生成和屏障特性以及控制这些过程的信号通路中具有内在异常。因此，我们的研究结果为神经退行性疾病提供了iPSC衍生的BBB模型，并证明了自主神经血管缺陷可能是HD病理学的基础，并对治疗和药物递送产生影响。Lim等人显示HD iPSC衍生的脑微血管内皮细胞具有受损的血管生成和屏障性质。转录组学分析为功能障碍的基础途径提供了机制性见解，WNT抑制可预防血管生成缺陷。该系统还提出了减少疾病负担和评估血液透析药物的血脑屏障渗透的策略。
Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington’s disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery. Lim et al. show that HD iPSCs-derived brain microvascular endothelial cells have impaired angiogenic and barrier properties. Transcriptomic analysis provides mechanistic insights into pathways that underlie dysfunction, and WNT inhibition prevents angiogenic deficits. This system also suggests strategies to reduce disease burden and assess BBB penetration of drugs for HD.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
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影响因子：
4.7
作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J
影响因子：
20.1
作者：
Chamorro-Jorganes A;Lee MY;Araldi E;Landskroner-Eiger S;Fernández-Fuertes M;Sahraei M;Quiles Del Rey M;van Solingen C;Yu J;Fernández-Hernando C;Sessa WC;Suárez Y
通讯作者：
Suárez Y