Human neural stem cell transplantation provides long-term restoration of neuronal plasticity in the irradiated hippocampus.
Human neural stem cell transplantation provides long-term restoration of neuronal plasticity in the irradiated hippocampus.
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DOI：
10.3727/096368914x684600
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发表时间：
2015
影响因子：
3.3
通讯作者：
Limoli CL
中科院分区：
文献类型：
--
作者：
Acharya MM;Rosi S;Jopson T;Limoli CL
对于大多数中枢神经系统恶性肿瘤，放疗提供了阻止肿瘤生长的最佳选择，但通常与衰弱和进行性认知功能障碍有关。尽管认识到这种严重的副作用，但目前还没有令人满意的长期解决方案，这促使我们努力探索颅骨干细胞移植的潜在治疗功效。我们已经证明，使用接受颅脑照射的无胸腺大鼠模型，人类神经干细胞（hNSC）的海马内移植可以提供持久的认知益处。为了探索移植细胞改善辐射诱导的认知功能障碍的能力的可能机制，我们分析了移植后 1 个月和 8 个月海马中行为诱导的活性调节细胞骨架相关蛋白 (Arc) 的表达模式。虽然免疫组织化学分析显示，受辐射大脑中一小部分（4.5%）存活的 hNSC 不表达神经元或星形胶质细胞标记物，但 hNSC 移植通过在两个时间点促进 Arc 的表达来影响宿主大脑受辐射的微环境。众所周知，Arc 在长期突触可塑性和记忆的神经元机制中发挥着关键作用，并为检测积极参与与记忆巩固相关的空间和上下文信息处理的神经元提供了可靠的标记。颅脑照射显着减少了照射后 1 个月和 8 个月表达行为诱导 Arc 的锥体神经元 (CA1) 和颗粒神经元 (DG) 的数量。 hNSC 移植恢复了宿主大脑中可塑性相关 Arc 的表达，以控制水平。这些发现表明，hNSC 移植促进宿主海马神经元的长期恢复，并表明促进辐射后认知保存的一种机制涉及来自移植细胞的营养支持。
For the majority of CNS malignancies, radiotherapy provides the best option for forestalling tumor growth, but is frequently associated with debilitating and progressive cognitive dysfunction. Despite the recognition of this serious side effect, satisfactory long-term solutions are not currently available and have prompted our efforts to explore the potential therapeutic efficacy of cranial stem cell transplants. We have demonstrated that intrahippocampal transplantation of human neural stem cells (hNSCs) can provide long-lasting cognitive benefits using an athymic rat model subjected to cranial irradiation. To explore the possible mechanisms underlying the capability of engrafted cells to ameliorate radiation-induced cognitive dysfunction we analyzed the expression patterns of the behaviorally induced activity-regulated cytoskeleton-associated protein (Arc) in the hippocampus at 1 and 8 months postgrafting. While immunohistochemical analyses revealed a small fraction (4.5%) of surviving hNSCs in the irradiated brain that did not express neuronal or astroglial makers, hNSC transplantation impacted the irradiated microenvironment of the host brain by promoting the expression of Arc at both time points. Arc is known to play key roles in the neuronal mechanisms underlying long-term synaptic plasticity and memory and provides a reliable marker for detecting neurons that are actively engaged in spatial and contextual information processing associated with memory consolidation. Cranial irradiation significantly reduced the number of pyramidal (CA1) and granule neurons (DG) expressing behaviorally induced Arc at 1 and 8 months postirradiation. Transplantation of hNSCs restored the expression of plasticity-related Arc in the host brain to control levels. These findings suggest that hNSC transplantation promotes the long-term recovery of host hippocampal neurons and indicates that one mechanism promoting the preservation of cognition after irradiation involves trophic support from engrafted cells.