Astrocyte-derived extracellular vesicles enhance the survival and electrophysiological function of human cortical neurons in vitro.
Astrocyte-derived extracellular vesicles enhance the survival and electrophysiological function of human cortical neurons in vitro.
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DOI：
10.1016/j.biomaterials.2021.120700
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发表时间：
2021-04
期刊：
影响因子：
14
通讯作者：
Kim DH
中科院分区：
文献类型：
--
作者：
Chun C;Smith AST;Kim H;Kamenz DS;Lee JH;Lee JB;Mack DL;Bothwell M;Clelland CD;Kim DH
人诱导多能干细胞来源的神经元是模拟神经病理生理学和筛选新的治疗化合物的临床前疗效/毒性的有力工具。然而，体外培养的人类神经元通常不能完全概括人类神经系统的生理学，特别是在表现出与成人神经元相当的形态成熟、寿命和电化学信号能力方面。在这项研究中，我们研究了星形胶质细胞来源的细胞外小泡(EVS)在体外调节人神经元存活和电生理功能的可能性。具体地说，我们证明了从人类星形胶质细胞获得的EVS在人类IPSC来源的皮质神经元的同质性群体中促进增强的单细胞电生理功能和抗凋亡行为。此外，还进行了EV-蛋白质组学分析，以确定具有促进所观察到的生理增强的潜力的货物蛋白。EV货物被发现包括神经保护蛋白，如热休克蛋白、α-突触核蛋白和脂蛋白受体相关蛋白1(LRP1)，以及负向调节神经元凋亡的载脂蛋白E(APOE)，以及支持神经元氧化应激管理的过氧化物素同系物。对神经元兴奋性和突触发育有正向调节作用的蛋白有钾通道四聚化结构域12(KCTD12)、葡萄糖-6-磷酸脱氢酶(G6PD)、激动素家族成员5B(KIF5B)、血影蛋白-α非红细胞1(SPTAN1)。这些物质对培养神经元电生理功能的显著改善和对细胞凋亡信号的明显抑制，可能对改进临床前的体外筛选方法具有重要意义。此外，我们收集的数据突出了基于EV的疗法作为未来治疗根深蒂固的中枢和周围神经疾病的潜在临床治疗类别的潜力。
Neurons derived from human induced pluripotent stem cells (hiPSCs) are powerful tools for modeling neural pathophysiology and preclinical efficacy/toxicity screening of novel therapeutic compounds. However, human neurons cultured in vitro typically do not fully recapitulate the physiology of the human nervous system, especially in terms of exhibiting morphological maturation, longevity, and electrochemical signaling ability comparable to that of adult human neurons. In this study, we investigated the potential for astrocyte-derived extracellular vesicles (EVs) to modulate survival and electrophysiological function of human neurons in vitro. Specifically, we demonstrate that EVs obtained from human astrocytes promote enhanced single cell electrophysiological function and anti-apoptotic behavior in a homogeneous population of human iPSC-derived cortical neurons. Furthermore, EV-proteomic analysis was performed to identify cargo proteins with the potential to promote the physiological enhancement observed. EV cargos were found to include neuroprotective proteins such as heat shock proteins, alpha-synuclein, and lipoprotein receptor-related protein 1 (LRP1), as well as apolipoprotein E (APOE), which negatively regulates neuronal apoptosis, and a peroxidasin homolog that supports neuronal oxidative stress management. Proteins that positively regulate neuronal excitability and synaptic development were also detected, such as potassium channel tetramerization domain containing 12 (KCTD12), glucose-6- phosphate dehydrogenase (G6PD), kinesin family member 5B (KIF5B), spectrin-alpha non-erythrocytic1 (SPTAN1). The remarkable improvements in electrophysiological function and evident inhibition of apoptotic signaling in cultured neurons exposed to these cargos may hold significance for improving preclinical in vitro screening modalities. In addition, our collected data highlight the potential for EV-based therapeutics as a potential class of future clinical treatment for tackling inveterate central and peripheral neuropathies.
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