Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
Instituto de Neurociencias de Alicante, Miguel Hernández-CSIC University, Sant Joan d'Alacant, Alicante, Spain.
JCI Insight. 2024 Feb 20;9(7):e174645. doi: 10.1172/jci.insight.174645.
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.
患有甲状腺激素（TH）细胞转运单羧酸转运蛋白 8（MCT8）基因突变的患者会出现严重的神经精神运动发育迟缓，称为 Allan-Herndon-Dudley 综合征（AHDS）。据推测，这是由于在宫内和产后发育阶段，大脑中 TH 信号的减少所致，而治疗仍然颇具挑战性。鉴于脑 TH 转运蛋白在物种间存在差异，以及在小鼠中进行研究的局限性，我们使用 MCT8 缺陷患者的人诱导多能干细胞（iPSC）生成了大脑类器官（CO）。MCT8 缺陷的 CO 表现出：（i）早期神经发育改变，导致神经玫瑰花结更小，皮质单位更薄；（ii）通过脱碘酶-3 介导的 T3 分解代谢，评估发育中的神经细胞中 T3 转运受损；（iii）涉及大脑皮层发育的基因表达减少；（iv）T3 诱导的 TH 调节基因减少。相比之下，TH 类似物 3,5-二碘甲状腺原氨酸和 3,3',5-三碘甲状腺原氨酸在 MCT8 缺陷的 CO 中引发了正常反应（T3 反应基因的诱导/抑制），这证明了缺乏 T3 转运是 AHDS 病理生理学的基础，并证明了 TH 类似物在治疗 AHDS 患者方面的临床潜力。MCT8 缺陷的 CO 代表了一种具有物种特异性的相关临床前模型，可用于筛选具有潜在益处的药物，作为针对 AHDS 患者的个体化治疗方法。
