Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the
Gad D Vatine1, Abraham Al-Ahmad2, Bianca K Barriga1
1The Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Insights
Mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) cause developmental delays. Using patient stem cells, researchers found MCT8 is crucial for TH transport across the blood-brain barrier (BBB), suggesting new therapeutic strategies.
Area of Science:
- Neuroendocrinology
- Stem Cell Biology
- Human Genetics
Background:
- Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) lead to severe psychomotor retardation.
- Existing animal models fail to accurately replicate the human disease's biological complexities.
Purpose of the Study:
- To investigate the role of MCT8 in thyroid hormone transport across the blood-brain barrier (BBB).
- To explore potential therapeutic strategies for MCT8 deficiency by assessing drug permeability across a patient-derived BBB model.
Main Methods:
- Generation of patient-specific induced pluripotent stem cells (iPSCs) to create MCT8-deficient neural cells.
- Development of an iPSC-based human blood-brain barrier (BBB) model to study TH transport.
- Assessment of TH influx and candidate drug permeability across the engineered BBB.
Main Results:
- MCT8-deficient neural cells exhibited normal intrinsic TH-dependent properties.
- MCT8 was identified as essential for the polarized transport of active TH across the BBB.
- A candidate therapeutic drug demonstrated limited ability to permeate the MCT8-deficient BBB model.
Conclusions:
- The blood-brain barrier (BBB) plays a critical role in the pathophysiology of MCT8 deficiency.
- Circumventing the compromised BBB to deliver active thyroid hormone (TH) directly to the brain represents a promising therapeutic avenue.
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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