PDF(Pubmed)
Abstract：
Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene. Dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis. Although the neurological sequelae of the disease are well established, little is known about how these mutations might affect cellular components and the function of the blood-brain barrier (BBB). We generated disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies. Using these microphysiological systems, we demonstrate that the BBB generated from TSC2 heterozygous mutant cells shows increased permeability which can be rescued by wild type astrocytes and with treatment with rapamycin, an mTOR kinase inhibitor. Our results further demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of the cell lineages contributing to TSC pathogenesis.
摘要：
结节性硬化症（TSC）是一种多系统遗传疾病，可引起大脑和其他重要器官的良性肿瘤。最令人衰弱的症状是由中枢神经系统受累引起的，并导致许多严重的症状，包括癫痫发作。智力残疾,自闭症,和行为问题。TSC是由TSC1或TSC2基因的杂合突变引起的。mTOR激酶的失调及其多方面的下游信号改变是疾病发病机制的核心。尽管这种疾病的神经系统后遗症已经得到了很好的证实，关于这些突变如何影响细胞成分和血脑屏障（BBB）的功能知之甚少。我们通过利用人类诱导多能干细胞和微流控细胞培养技术产生了BBB的疾病特异性细胞模型。利用这些微生理系统，我们证明，从TSC2杂合突变细胞产生的BBB显示出增加的通透性，这可以通过野生型星形胶质细胞和雷帕霉素治疗来拯救，mTOR激酶抑制剂。我们的结果进一步证明了微生理系统在研究人类神经系统疾病和增进我们对有助于TSC发病机理的细胞谱系的认识方面的实用性。
