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Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier.
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.
Afiliação
  • Vatine GD; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Al-Ahmad A; Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
  • Barriga BK; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Svendsen S; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Salim A; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Garcia L; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Garcia VJ; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Ho R; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Yucer N; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Qian T; Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Lim RG; Department of Biological Chemistry, University of California, Irvine (UCI), Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI), Irvine, CA 92697, USA.
  • Wu J; Department of Biological Chemistry, University of California, Irvine (UCI), Irvine, CA 92697, USA.
  • Thompson LM; Department of Biological Chemistry, University of California, Irvine (UCI), Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine (UCI), Irvine, CA 92697, USA; Department of Neurobiology and Behavior, University of California, Irvine (UC
  • Spivia WR; Advanced Clinical Biosystems Research Institute, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Chen Z; Advanced Clinical Biosystems Research Institute, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Van Eyk J; Advanced Clinical Biosystems Research Institute, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Palecek SP; Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • Refetoff S; Department of Medicine, Pediatrics and Committee on Genetics, The University of Chicago, Chicago, IL 60637, USA.
  • Shusta EV; Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: eshusta@wisc.edu.
  • Svendsen CN; The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: clive.svendsen@cshs.org.
Cell Stem Cell ; 20(6): 831-843.e5, 2017 06 01.
Article em En | MEDLINE | ID: mdl-28526555
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos Psicomotores / Barreira Hematoencefálica / Transportadores de Ácidos Monocarboxílicos / Células-Tronco Pluripotentes Induzidas / Neurônios Limite: Female / Humans / Male Idioma: En Revista: Cell Stem Cell Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transtornos Psicomotores / Barreira Hematoencefálica / Transportadores de Ácidos Monocarboxílicos / Células-Tronco Pluripotentes Induzidas / Neurônios Limite: Female / Humans / Male Idioma: En Revista: Cell Stem Cell Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos