期刊
STEM CELLS
卷 34, 期 4, 页码 1040-1053出版社
WILEY
DOI: 10.1002/stem.2273
关键词
Stem cell; Oligodendrocyte; Electrophysiology; Human; Amyotrophic lateral sclerosis; oligodendrocyte precursor cell
资金
- Wellcome Trust [092742/Z/10/Z]
- Medical Research Council [MR/J004367/1]
- MNDA
- NC3Rs
- Multiple Sclerosis Trials Collaboration
- Department of Biotechnology, Government of India
- Patrick Wild Centre/RS Macdonald Trust
- Royal Society of Edinburgh/Caledonian Research Fund Personal Research Fellowship
- MRC [G0300329, G0500289, G0902044, MR/J004367/1, MC_G1000733, G0900688] Funding Source: UKRI
- Medical Research Council [G0902044, MC_G1000733, G0300329, G0900688, G0500289, MR/J004367/1] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/C011202/1] Funding Source: researchfish
- Wellcome Trust [092742/Z/10/Z] Funding Source: Wellcome Trust
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. Stem Cells2016;34:1040-1053
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