2. Academic Validation
  3. 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

  • Cell Stem Cell. 2017 Jun 1;20(6):831-843.e5. doi: 10.1016/j.stem.2017.04.002.
Gad D Vatine 1,  Abraham Al-Ahmad 2,  Bianca K Barriga 1,  Soshana Svendsen 1,  Ariel Salim 1,  Leslie Garcia 1,  Veronica J Garcia 1,  Ritchie Ho 1,  Nur Yucer 1,  Tongcheng Qian 3,  Ryan G Lim 4,  Jie Wu 5,  Leslie M Thompson 6,  Weston R Spivia 7,  Zhaohui Chen 7,  Jennifer Van Eyk 7,  Sean P Palecek 3,  Samuel Refetoff 8,  Eric V Shusta 9,  Clive N Svendsen 10
Affiliations

Affiliations

  • 1 The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 2 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.
  • 3 Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA.
  • 4 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.
  • 5 Department of Biological Chemistry, University of California, Irvine (UCI), Irvine, CA 92697, USA.
  • 6 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 (UCI), Irvine, CA 92697, USA; Department of Psychiatry and Human Behavior, University of California, Irvine (UCI), Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine (UCI), Irvine, CA 92697, USA.
  • 7 Advanced Clinical Biosystems Research Institute, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 8 Department of Medicine, Pediatrics and Committee on Genetics, The University of Chicago, Chicago, IL 60637, USA.
  • 9 Department of Chemical and Biological Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: eshusta@wisc.edu.
  • 10 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.
PMID: 28526555 DOI: 10.1016/j.stem.2017.04.002
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.

Keywords

MCT8; T3; blood brain barrier; disease model; iPSC; induced pluripotent stem cells; monocarboxyl transporter 8; neuronal maturation; thyroid; thyroid hormone.

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