Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination

Jae Young Lee, Min Joung Kim, Devy Deliyanti, Michael F. Azari, Fernando Rossello, Adam Costin, Georg Ramm, Edouard G. Stanley, Andrew G. Elefanty, Jennifer L. Wilkinson-Berka, Steven Petratos

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20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)122-135
Number of pages14
JournalEBioMedicine
Volume25
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • Allan-Herndon-Dudley syndrome
  • Di-iodothyropropionic acid (DITPA)
  • Human embryonic stem cells
  • Monocarboxylate transporter 8
  • NKX2.1
  • Oligodendrocytes
  • Thyroid hormone

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