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Lee, Jae Young; Kim, Min Joung; Deliyanti, Devy; Azari, Michael F.; Rossello, Fernando; Costin, Adam; Ramm, Georg; Stanley, Edouard G.; Elefanty, Andrew G.; Wilkinson-Berka, Jennifer L.; Petratos, Steven
EBioMedicine, 11/2017, Letnik: 25, Številka: CJournal Article
Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X-linked-inherited psychomotor retardation and hypomyelination disorder, Allan-Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS. Display omitted •NKX2.1-based sorting enhances OL derivation from hESC•MCT8 is required for the survival of OL precursor cells•DITPA promotes OL differentiation and myelination•DITPA overrides SLC16A2 (MCT8) down-regulation to potentiate myelination Thyroid hormone is vital for oligodendrocyte differentiation and myelination. Lee and colleagues show that MCT8 is an integral thyroid hormone transporter for oligodendrocytes derived from human embryonic stem cells. Knockdown of this transporter induces apoptosis of OLs, which could be prevented by the provision of DITPA.
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in: SICRIS
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