Department of Physics and Astronomy, Vanderbilt University, Nashville, USA.
Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, USA.
J Neurodev Disord. 2024 May 23;16(1):27. doi: 10.1186/s11689-024-09543-y.
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 and 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 TSC disease-specific cell models of the BBB by leveraging human induced pluripotent stem cell and microfluidic cell culture technologies.
Using microphysiological systems, we demonstrate that a BBB generated from TSC2 heterozygous mutant cells shows increased permeability. This can be rescued by wild type astrocytes or by treatment with rapamycin, an mTOR kinase inhibitor.
Our results demonstrate the utility of microphysiological systems to study human neurological disorders and advance our knowledge of cell lineages contributing to TSC pathogenesis and informs future therapeutics.
结节性硬化症（TSC）是一种多系统遗传疾病，可导致大脑和其他重要器官的良性肿瘤。最使人虚弱的症状源于中枢神经系统的受累，并导致多种严重症状，包括癫痫、智力障碍、自闭症和行为问题。TSC 是由 TSC1 或 TSC2 基因突变引起的杂合子突变引起的，mTOR 激酶的失调及其下游信号改变的多方面变化是疾病发病机制的核心。尽管该疾病的神经后遗症已得到充分证实，但对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。
我们利用人诱导多能干细胞和微流控细胞培养技术，生成了 TSC 特异性的 BBB 细胞模型。
使用微生理系统，我们证明了源自 TSC2 杂合突变细胞的 BBB 表现出增加的通透性。这种通透性可以通过野生型星形胶质细胞或通过施用雷帕霉素（一种 mTOR 激酶抑制剂）来挽救。
我们的结果证明了微生理系统在研究人类神经疾病方面的实用性，并增进了我们对导致 TSC 发病机制的细胞谱系的认识，并为未来的治疗提供了信息。
