Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes.
Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes.
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DOI：
10.1002/stem.2273
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Chandran S
中科院分区：
文献类型：
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作者：
Livesey MR;Magnani D;Cleary EM;Vasistha NA;James OT;Selvaraj BT;Burr K;Story D;Shaw CE;Kind PC;Hardingham GE;Wyllie DJ;Chandran S
基于啮齿动物的研究表明，少突胶质细胞的膜特性在其生理和从少突胶质前体细胞（OPC）成熟过程中起着重要作用。然而，尽管人类少突胶质细胞的功能障碍与人类神经退行性疾病（如多发性硬化症（MS）和肌萎缩侧索硬化症（ALS））有关，但这些特性和成熟过程在人类少突胶质细胞中的保存情况仍然未知。在这里，我们定义了来自多能干细胞的人类少突胶质细胞从OPC阶段成熟时的膜特性，并确定了在啮齿动物系统中报道的成熟特异性生理特征的强保守性。我们发现，随着人类少突胶质细胞发育和表达成熟标记物，它们表现出电压门控钠和钾通道的逐渐减少，以及河豚毒素敏感尖峰活性的丧失。与此同时，内整流钾通道活性增加，以及AMPA受体组成的特征开关。所有这些步骤都反映了在啮齿动物系统中观察到的发育轨迹。从携带突变体C9ORF72‐的ALS患者诱导的多能干细胞中提取的少突胶质细胞，尽管存在RNA灶，但与对照系相比，并未表现出成熟障碍，并保持了活力，这表明成熟缺陷可能不是该突变的主要特征。因此，我们已经确定，人类少突胶质细胞膜特性的发育与啮齿动物细胞中的特性非常相似，并为研究人类神经退行性疾病引起的突变对少突胶质细胞成熟的影响提供了一个平台。干细胞2016；34:1040 - 1053
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 Cells 2016;34:1040–1053