Intrinsic blood-brain barrier dysfunction contributes to multiple sclerosis pathogenesis.
Intrinsic blood-brain barrier dysfunction contributes to multiple sclerosis pathogenesis.
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内在的血脑屏障功能障碍导致多发性硬化症的发病机制。
DOI：
10.1093/brain/awac019
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Engelhardt,Britta
中科院分区：
文献类型：
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作者：
Nishihara,Hideaki;Perriot,Sylvain;Gastfriend,BenjaminD;Steinfort,Marel;Cibien,Celine;Soldati,Sasha;Matsuo,Kinya;Guimbal,Sarah;Mathias,Amandine;Palecek,SeanP;Shusta,EricV;Pasquier,RenaudDu;Engelhardt,Britta
血脑屏障（BBB）的破坏和免疫细胞浸润到中枢神经系统是多发性硬化症（MS）的早期标志。导致BBB功能障碍的机制还不完全清楚，通常认为是neuroniphilosis. There的后果，我们已经挑战了这一观点，并询问是否内在的改变，在MS患者的BBB MS发病机制。为此，我们利用来自健康对照和MS患者的人诱导多能干细胞，并将其分化为脑微血管内皮细胞（BMEC）样细胞作为BBB的体外模型。与健康对照相比，MS衍生的BMEC样细胞显示出受损的连接完整性、屏障特性和外排泵活性。此外，MS衍生的BMEC样细胞表现出炎性表型，粘附分子表达和免疫细胞相互作用增加。MS来源的内皮祖细胞中Wnt/β-catenin信号的激活增强了屏障特性，减少了炎症表型。我们的研究为MS患者BBB功能的内在损伤提供了证据，该损伤可以在体外模拟。因此，人iPSC衍生的BMEC样细胞适合于探索MS中BBB功能障碍的分子基础，并将有助于鉴定用于BBB稳定的潜在新治疗靶点。
Blood–brain barrier (BBB) breakdown and immune cell infiltration into the CNS are early hallmarks of multiple sclerosis (MS). The mechanisms leading to BBB dysfunction are incompletely understood and generally thought to be a consequence of neuroinflammation.Here, we have challenged this view and asked if intrinsic alterations in the BBB of MS patients contribute to MS pathogenesis. To this end, we made use of human induced pluripotent stem cells derived from healthy controls and MS patients and differentiated them into brain microvascular endothelial cell (BMEC)-like cells asin vitromodel of the BBB. MS-derived BMEC-like cells showed impaired junctional integrity, barrier properties and efflux pump activity when compared to healthy controls. Also, MS-derived BMEC-like cells displayed an inflammatory phenotype with increased adhesion molecule expression and immune cell interactions. Activation of Wnt/β-catenin signalling in MS-derived endothelial progenitor cells enhanced barrier characteristics and reduced the inflammatory phenotype.Our study provides evidence for an intrinsic impairment of BBB function in MS patients that can be modelledin vitro. Human iPSC-derived BMEC-like cells are thus suitable to explore the molecular underpinnings of BBB dysfunction in MS and will assist in the identification of potential novel therapeutic targets for BBB stabilization.