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
Affiliations
Jae Young Lee
Department of Medicine, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia
Min Joung Kim
Department of Medicine, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia
Devy Deliyanti
Department of Diabetes, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia
Michael F. Azari
School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia
Fernando Rossello
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia
Adam Costin
The Clive & Vera Ramaciotti Centre for Cryo Electron Microscopy, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia
Georg Ramm
The Clive & Vera Ramaciotti Centre for Cryo Electron Microscopy, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia
Edouard G. Stanley
Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia
Andrew G. Elefanty
Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia
Jennifer L. Wilkinson-Berka
Department of Diabetes, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia
Steven Petratos
Department of Medicine, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia
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.
