Anti-Muscarinic Adjunct Therapy Accelerates Functional Human Oligodendrocyte Repair
Anti-Muscarinic Adjunct Therapy Accelerates Functional Human Oligodendrocyte Repair
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DOI：
10.1523/jneurosci.3510-14.2015
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发表时间：
2015-02-25
影响因子：
5.3
通讯作者：
Sim, Fraser J.
中科院分区：
文献类型：
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作者：
Abiraman, Kavitha;Pol, Suyog U.;Sim, Fraser J.
髓鞘疾病的治疗性修复可能受到人类少突胶质细胞分化相对缓慢的限制。为了确定直接加速人少突胶质细胞祖细胞（hOPC）分化的适当药理学靶点，我们使用基于CD 140 a/O 4的人前脑FACS和hOPC特异性受体的微阵列。其中，我们确定CHRM 3，M3 R毒蕈碱乙酰胆碱受体，作为限制少突胶质细胞偏向的CD 140 a（+）O 4（+）细胞。毒蕈碱激动剂处理hOPC导致少突胶质细胞定型的特异性和剂量依赖性阻断。相反，当hOPC与人神经元共培养时，M3 R拮抗剂处理刺激少突胶质细胞分化。用FDA批准的毒蕈碱受体拮抗剂索利那新全身治疗，增加了移植的hOPC在低髓鞘化shiverer/rag 2脑中的少突胶质细胞分化。重要的是，索利那新治疗的移植动物减少听觉脑干反应峰间潜伏期，增加传导速度，从而增强功能修复的指示。因此，索利那新和其他选择性毒蕈碱拮抗剂代表了通过移植的人祖细胞加速修复的新的辅助方法。
Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a(+)O4(+) cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors.