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Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier
Cell Stem Cell ( IF 23.9 ) Pub Date : 2017-05-16 00:00:00 , DOI: 10.1016/j.stem.2017.04.002
Gad D. Vatine , Abraham Al-Ahmad , Bianca K. Barriga , Soshana Svendsen , Ariel Salim , Leslie Garcia , Veronica J. Garcia , Ritchie Ho , Nur Yucer , Tongcheng Qian , Ryan G. Lim , Jie Wu , Leslie M. Thompson , Weston R. Spivia , Zhaohui Chen , Jennifer Van Eyk , Sean P. Palecek , Samuel Refetoff , Eric V. Shusta , Clive N. Svendsen

Inactivating mutations in the thyroid hormone (TH) transporterMonocarboxylate transporter 8(MCT8) cause severe psychomotor retardation in children. Animal models do not reflect the biology of the human disease. Using patient-specific induced pluripotent stem cells (iPSCs), we generated MCT8-deficient neural cells that showed normal TH-dependent neuronal properties and maturation. However, the blood-brain barrier (BBB) controls TH entry into the brain, and reduced TH availability to neural cells could instead underlie the diseased phenotype. To test potential BBB involvement, we generated an iPSC-based BBB model of MCT8 deficiency, and we found that MCT8 was necessary for polarized influx of the active form of TH across the BBB. We also found that a candidate drug did not appreciably cross the mutant BBB. Our results therefore clarify the underlying physiological basis of this disorder, and they suggest that circumventing the diseased BBB to deliver active TH to the brain could be a viable therapeutic strategy.

中文翻译:

使用来自MCT8缺陷患者的iPSC对精神运动迟缓进行建模表明血脑屏障的重要作用

甲状腺激素(TH)转运蛋白的失活突变单羧酸酯转运蛋白8(MCT8)会导致儿童严重的精神运动发育迟缓。动物模型不能反映人类疾病的生物学特性。使用患者特异性诱导的多能干细胞(iPSC),我们生成了MCT8缺陷型神经细胞,显示出正常的TH依赖性神经元特性和成熟度。但是,血脑屏障(BBB)控制着TH进入大脑,而减少了TH向神经细胞的利用率,可能是患病表型的基础。为了测试潜在的BBB参与,我们生成了一个基于iPSC的MCT8缺乏症的BBB模型,我们发现MCT8对于TH的活性形式通过BBB的极化流入是必需的。我们还发现候选药物未明显穿过突变体BBB。
更新日期:2017-06-12
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