Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome

Abstract

Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 ( MCT8 ) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3–mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3′,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.

Spatiotemporal expression of thyroid hormone transporter MCT8 and THRA mRNA in human cerebral organoids recapitulating first trimester cortex development

“…As a first step towards such disease modelling, we recently used genome editing to generate several novel isogenic hiPSC lines carrying missense and nonsense MCT8 mutations 69 . Notably, a proof-of-concept study 70 was recently published when our paper was in the final phase of peer review. The authors showed that MCT8-deficient hiPSC lines can be differentiated into hCO displaying impaired T3 uptake.…”

“…The authors showed that MCT8-deficient hiPSC lines can be differentiated into hCO displaying impaired T3 uptake. A very preliminary phenotyping of different hCOs suggests that MCT8 deficiency altered neuronal progenitor dynamics resulting in smaller size neural rosettes and overall thinner cortical units 70 . One should note, however, that the absence of structures recapitulating blood–brain-barrier function in current hCO models will limit any modelling efforts of MCT8 deficiency to the analysis of consequences resulting from deficient TH uptake by neural cells.…”