Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier.
Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier.
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DOI：
10.1016/j.stem.2017.04.002
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发表时间：
2017-06-01
期刊：
影响因子：
23.9
通讯作者：
Svendsen CN
中科院分区：
文献类型：
--
作者：
Vatine GD;Al-Ahmad A;Barriga BK;Svendsen S;Salim A;Garcia L;Garcia VJ;Ho R;Yucer N;Qian T;Lim RG;Wu J;Thompson LM;Spivia WR;Chen Z;Van Eyk J;Palecek SP;Refetoff S;Shusta EV;Svendsen CN
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. Vatine et al. show that human iPSC-based modeling can pinpoint the origin of a neuronal disorder in the brain as a defect in transport of thyroid hormone across the blood-brain barrier, rather than in the neurons themselves.
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影响因子：
8.8
作者：
Lim RG;Quan C;Reyes-Ortiz AM;Lutz SE;Kedaigle AJ;Gipson TA;Wu J;Vatine GD;Stocksdale J;Casale MS;Svendsen CN;Fraenkel E;Housman DE;Agalliu D;Thompson LM
通讯作者：
Thompson LM
DOI：
10.1038/mt.2015.220
发表时间：
2016-03
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Bakondi B;Lv W;Lu B;Jones MK;Tsai Y;Kim KJ;Levy R;Akhtar AA;Breunig JJ;Svendsen CN;Wang S
通讯作者：
Wang S
影响因子：
9.8
作者：
Dumitrescu, AM;Liao, XH;Refetoff, S
通讯作者：
Refetoff, S
影响因子：
4.8
作者：
Ferrara, Alfonso Massimiliano;Liao, Xiao-Hui;Refetoff, Samuel
通讯作者：
Refetoff, Samuel
DOI：
10.1016/j.mcn.2012.03.007
发表时间：
2012-05
期刊：
Molecular and cellular neurosciences
影响因子：
--
作者：
Dugas JC;Ibrahim A;Barres BA
通讯作者：
Barres BA