title: Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes.
abstract: Rodent-based studies have shown that the membrane properties of oligodendrocytes play prominent roles in their physiology and shift markedly during their maturation from the oligodendrocyte precursor cell (OPC) stage. However, the conservation of these properties and maturation processes in human oligodendrocytes remains unknown, despite their dysfunction being implicated in human neurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Here, we have defined the membrane properties of human oligodendrocytes derived from pluripotent stem cells as they mature from the OPC stage, and have identified strong conservation of maturation-specific physiological characteristics reported in rodent systems. We find that as human oligodendrocytes develop and express maturation markers, they exhibit a progressive decrease in voltage-gated sodium and potassium channels and a loss of tetrodotoxin-sensitive spiking activity. Concomitant with this is an increase in inwardly rectifying potassium channel activity, as well as a characteristic switch in AMPA receptor composition. All these steps mirror the developmental trajectory observed in rodent systems. Oligodendrocytes derived from mutant C9ORF72-carryng ALS patient induced pluripotent stem cells did not exhibit impairment to maturation and maintain viability with respect to control lines despite the presence of RNA foci, suggesting that maturation defects may not be a primary feature of this mutation. Thus, we have established that the development of human oligodendroglia membrane properties closely resemble those found in rodent cells and have generated a platform to enable the impact of human neurodegenerative disease-causing mutations on oligodendrocyte maturation to be studied.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Livesey
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Dario
authors.initials: D
authors.lastname: Magnani
authors.affiliation: Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Cleary
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Navneet A
authors.initials: NA
authors.lastname: Vasistha
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, India.
authors.forename: Owain T
authors.initials: OT
authors.lastname: James
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Bhuvaneish T
authors.initials: BT
authors.lastname: Selvaraj
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Burr
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Story
authors.affiliation: Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, United Kingdom.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, India.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Kind
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, India.
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.affiliation: Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.|MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, India.
authors.forename: Siddharthan
authors.initials: S
authors.lastname: Chandran
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D055724:Electrophysiological Phenomena; D005260:Female; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000473:pathology / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D061566:Voltage-Gated Sodium Channels / Q000235:genetics
chemical_list: D024642:Potassium Channels, Voltage-Gated; D061566:Voltage-Gated Sodium Channels
keywords: Amyotrophic lateral sclerosis; Electrophysiology; Human; Oligodendrocyte; Stem cell; oligodendrocyte precursor cell