Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes.
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.
['Livesey|Matthew R|MR|', 'Magnani|Dario|D|', 'Cleary|Elaine M|EM|', 'Vasistha|Navneet A|NA|', 'James|Owain T|OT|', 'Selvaraj|Bhuvaneish T|BT|', 'Burr|Karen|K|', 'Story|David|D|', 'Shaw|Christopher E|CE|', 'Kind|Peter C|PC|', 'Hardingham|Giles E|GE|', 'Wyllie|David J A|DJ|', 'Chandran|Siddharthan|S|']
D000690:Amyotrophic Lateral Sclerosis D000818:Animals D002454:Cell Differentiation D055724:Electrophysiological Phenomena D005260:Female D006801:Humans D008297:Male D009103:Multiple Sclerosis D009154:Mutation D055495:Neurogenesis D009836:Oligodendroglia D039904:Pluripotent Stem Cells D024642:Potassium Channels, Voltage-Gated D061566:Voltage-Gated Sodium Channels
Electrophysiology Human Oligodendrocyte oligodendrocyte precursor cell Amyotrophic lateral sclerosis Stem cell