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. Epub 2017 May 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Cell Line
  • Female
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Monocarboxylic Acid Transporters / deficiency*
  • Neurons / metabolism*
  • Neurons / pathology
  • Psychomotor Disorders / genetics
  • Psychomotor Disorders / metabolism*
  • Psychomotor Disorders / pathology

Substances

  • Monocarboxylic Acid Transporters
  • SLC16A2 protein, human