Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain
Intranasally Administered Human MSC-Derived Extracellular Vesicles Pervasively Incorporate into Neurons and Microglia in both Intact and Status Epilepticus Injured Forebrain
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DOI：
10.3390/ijms21010181
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Shetty, Ashok K.
中科院分区：
文献类型：
--
作者：
Kodali, Maheedhar;Castro, Olagide W.;Shetty, Ashok K.
源自人骨髓间充质干细胞 (hMSC) 的细胞外囊泡 (EV) 由于其强大的抗炎和神经保护特性，作为治疗神经系统和神经退行性疾病的生物制剂具有广阔的前景。此外，EV的鼻内（IN）给药引起了广泛关注，因为该过程是无创的，适合重复分配，并且可以使EV快速渗透到前脑的多个区域。尽管如此，尚不清楚脑损伤诱导的信号对于 IN 给药的 EV 进入不同大脑区域是否至关重要。因此，在这项研究中，我们研究了 IN 施用的 hMSC 衍生的 EV 在完整和癫痫持续状态 (SE) 损伤的大鼠前脑中的神经元和小胶质细胞中的分布。将 100 亿个标记有 PKH26 的 EV 单侧分配到幼稚大鼠和经历了两小时红藻氨酸诱导 SE 的大鼠的左鼻孔中。六小时后，使用针对不同神经细胞标记物处理的连续脑切片和共聚焦显微镜对多个前脑区域的 PKH26 + EV 进行量化。值得注意的是，几乎所有完好和 SE 损伤前脑的双侧区域均可见 EV。对于大多数前脑区域来说，包含 EV 的神经元的百分比是相当的。然而，在经历 SE 的动物中，海马 CA1 亚区和内嗅皮层中神经元掺入 EV 的比例较高，这些区域通常在 SE 后表现出神经退行性变。相比之下，小胶质细胞对 EV 的整合在测量的前脑的每个区域都具有高度可比性。因此，EV 的单侧 IN 给药可有效地将 EV 双边递送到完整或受损前脑多个区域的神经元和小胶质细胞中。此外，在脑损伤区域，神经元对 EV 的掺入量更高，这意味着损伤相关信号可能在将 EV 靶向神经元中发挥作用，这可能有利于各种神经退行性疾病（包括创伤性脑损伤、中风、多发性硬化症和阿尔茨海默病）的 EV 治疗。
Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stem cells (hMSCs) have great promise as biologics to treat neurological and neurodegenerative conditions due to their robust antiinflammatory and neuroprotective properties. Besides, intranasal (IN) administration of EVs has caught much attention because the procedure is noninvasive, amenable for repetitive dispensation, and leads to a quick penetration of EVs into multiple regions of the forebrain. Nonetheless, it is unknown whether brain injury-induced signals are essential for the entry of IN-administered EVs into different brain regions. Therefore, in this study, we investigated the distribution of IN-administered hMSC-derived EVs into neurons and microglia in the intact and status epilepticus (SE) injured rat forebrain. Ten billion EVs labeled with PKH26 were dispensed unilaterally into the left nostril of naive rats, and rats that experienced two hours of kainate-induced SE. Six hours later, PKH26 + EVs were quantified from multiple forebrain regions using serial brain sections processed for different neural cell markers and confocal microscopy. Remarkably, EVs were seen bilaterally in virtually all regions of intact and SE-injured forebrain. The percentage of neurons incorporating EVs were comparable for most forebrain regions. However, in animals that underwent SE, a higher percentage of neurons incorporated EVs in the hippocampal CA1 subfield and the entorhinal cortex, the regions that typically display neurodegeneration after SE. In contrast, the incorporation of EVs by microglia was highly comparable in every region of the forebrain measured. Thus, unilateral IN administration of EVs is efficient for delivering EVs bilaterally into neurons and microglia in multiple regions in the intact or injured forebrain. Furthermore, incorporation of EVs by neurons is higher in areas of brain injury, implying that injury-related signals likely play a role in targeting of EVs into neurons, which may be beneficial for EV therapy in various neurodegenerative conditions including traumatic brain injury, stroke, multiple sclerosis, and Alzheimer's disease.