Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier

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

Research output: Contribution to journalArticlepeer-review

142 Scopus citations


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.

Original languageEnglish
Pages (from-to)831-843.e5
JournalCell Stem Cell
Issue number6
StatePublished - 1 Jun 2017
Externally publishedYes


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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology


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