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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Neuropharmacological properties of neurons derived from human stem cells.
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Neuropharmacological properties of neurons derived from human stem cells.

机译：源自人干细胞的神经元的神经药理特性。

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Human pluripotent stem cells have enormous potential value in neuropharmacology and drug discovery yet there is little data on the major classes and properties of receptors and ion channels expressed by neurons derived from these stem cells. Recent studies in this lab have therefore used conventional patch-clamp electrophysiology to investigate the pharmacological properties of the ligand and voltage-gated ion channels in neurons derived and maintained in vitro from the human stem cell (hSC) line, TERA2.cl.SP12. TERA2.cl.SP12 stem cells were differentiated with retinoic acid and used in electrophysiological experiments 28-50 days after beginning differentiation. HSC-derived neurons generated large whole cell currents with depolarizing voltage steps (-80 to 30 mV) comprised of an inward, rapidly inactivating component and a delayed, slowly deactivating outward component. The fast inward current was blocked by the sodium channel blocker tetrodotoxin (0.1 muM) and the outward currents were significantly reduced by tetraethylammonium ions (TEA, 5 mM) consistent with the presence of functional Na and K ion channels. Application of the inhibitory neurotransmitters, GABA (0.1-1000 muM) or glycine (0.1-1000 muM) evoked concentration dependent currents. The GABA currents were inhibited by the convulsants, picrotoxin (10 muM) and bicuculline (3 muM), potentiated by the NSAID mefenamic acid (10-100 muM), the general anaesthetic pentobarbital (100 muM), the neurosteroid allopregnanolone and the anxiolytics chlordiazepoxide (10 muM) and diazepam (10 muM) all consistent with the expression of GABA(A) receptors. Responses to glycine were reversibly blocked by strychnine (10 muM) consistent with glycine-gated chloride channels. The excitatory agonists, glutamate (1-1000 muM) and NMDA (1-1000 muM) activated concentration-dependent responses from hSC-derived neurons. Glutamate currents were inhibited by kynurenic acid (1 mM) and NMDA responses were blocked by MgCl(2) (2 mM) in a highly voltage-dependent manner. Together, these findings show that neurons derived from human stem cells develop an array of functional receptors and ion channels with a pharmacological profile in keeping with that described for native neurons. This study therefore provides support for the hypothesis that stem cells may provide a powerful source of human neurons for future neuropharmacological studies.
机译：人类多能干细胞在神经药理学和药物发现中具有巨大的潜在价值，但是关于由这些干细胞衍生的神经元表达的受体和离子通道的主要类别和特性的数据很少。因此，该实验室中的最新研究已使用常规的膜片钳电生理学来研究源自人干细胞（hSC）系TERA2.cl.SP12的神经元中配体和电压门控离子通道的药理特性。用视黄酸分化TERA2.cl.SP12干细胞，并在分化开始后28-50天用于电生理实验。 HSC衍生的神经元产生较大的全细胞电流，其去极化电压阶跃（-80至30 mV）包括向内的，快速失活的成分和延迟的，缓慢地失活的向外成分。快速的内向电流被钠通道阻滞剂河豚毒素（0.1μM）阻断，而外向电流被四乙铵离子（TEA，5 mM）显着降低，这与功能性的Na和K离子通道一致。施加抑制性神经递质，GABA（0.1-1000μM）或甘氨酸（0.1-1000μM）会引起浓度依赖性电流。 GABA电流被惊厥药微毒素（10μM）和双小分子（3μM）抑制，被NSAID甲芬那酸（10-100μM），全身麻醉的戊巴比妥（100μM），神经甾体去甲烯丙炔诺酮和抗焦虑药氯二氮卓增效。 （10μM）和地西epa（10μM）均与GABA（A）受体的表达一致。与甘氨酸控制氯离子通道一致的士的宁（10μM）可逆地阻断了对甘氨酸的反应。兴奋性激动剂谷氨酸（1-1000μM）和NMDA（1-1000μM）激活了hSC衍生神经元的浓度依赖性反应。谷氨酸电流被犬尿酸（1 mM）抑制，NMDA反应被MgCl（2）（2 mM）以高度电压依赖的方式阻止。总之，这些发现表明，源自人类干细胞的神经元形成了一系列功能性受体和离子通道，其药理学特征与针对天然神经元的描述一致。因此，这项研究为以下假设提供了支持：干细胞可能为未来的神经药理学研究提供强大的人类神经元来源。

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