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首页> 外文期刊>Cell stem cell >Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier
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Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier

机译：使用来自MCT8缺陷患者的IPSCS模拟精神脉冲延迟表明血脑屏障对血脑屏障的突出作用

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摘要

Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate 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.
机译：甲状腺激素（Th）转运蛋白转运蛋白转运蛋白8（MCT8）的灭活突变导致儿童严重的精神抑制。动物模型不反映人类疾病的生物学。使用患者特异性诱导的多能干细胞（IPSC），我们产生了MCT8缺陷的神经细胞，所述神经细胞显示正常的Th依赖性神经元特性和成熟。然而，血脑屏障（BBB）进入大脑进入大脑，并降低了神经细胞的可用性，而是可以使患病表型提高。为了测试潜在的BBB参与，我们生成了基于IPSC的MCT8缺乏的BBB模型，发现MCT8是在BBB上偏振中的偏振中涌入所必需的。我们还发现候选药物并未明显过于突变体BBB。因此，我们的结果阐明了这种疾病的潜在的生理基础，他们表明，旨在将患病的BBB赋予大脑活跃，可能是一种可行的治疗策略。

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  • 来源
    《Cell stem cell》 |2017年第6期|共18页
  • 作者

    Vatine Gad D.; Al-Ahmad Abraham; Barriga Bianca K.; Svendsen Soshana; Salim Ariel; Garcia Leslie; Garcia Veronica J.; Ho Ritchie; Yucer Nur; Qian Tongcheng; Lim Ryan G.; Wu Jie; Thompson Leslie M.; Spivia Weston R.; Chen Zhaohui; Van Eyk Jennifer; Palecek Sean P.; Refetoff Samuel; Shusta Eric V.; Svendsen Clive N.;

  • 作者单位

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Univ Wisconsin Dept Chem &

    Biol Engn Madison WI 53706 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

    Univ Wisconsin Dept Chem &

    Biol Engn Madison WI 53706 USA;

    Univ Calif Irvine Dept Biol Chem Irvine CA 92697 USA;

    Univ Calif Irvine Dept Biol Chem Irvine CA 92697 USA;

    Univ Calif Irvine Dept Biol Chem Irvine CA 92697 USA;

    Cedars Sinai Med Ctr Inst Heart Adv Clin Biosyst Res Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Inst Heart Adv Clin Biosyst Res Inst Los Angeles CA 90048 USA;

    Cedars Sinai Med Ctr Inst Heart Adv Clin Biosyst Res Inst Los Angeles CA 90048 USA;

    Univ Wisconsin Dept Chem &

    Biol Engn Madison WI 53706 USA;

    Univ Chicago Dept Med Pediat &

    Comm Genet Chicago IL 60637 USA;

    Univ Wisconsin Dept Chem &

    Biol Engn Madison WI 53706 USA;

    Cedars Sinai Med Ctr Board Governors Regenerat Med Inst Los Angeles CA 90048 USA;

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  • 正文语种 eng
  • 中图分类 细胞生物学;
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