MRI Tracking of Stem Cell Migration During Brain Injury

描述（由申请人提供）： 利用内源性神经干细胞（neural stem cells，NSCs）修复受损的神经元和胶质细胞是治疗脑损伤和多种神经系统疾病的一种有效方法。为了研究小鼠模型中神经干细胞对脑损伤的反应，我们正在开发micro-MRI方法来标记和跟踪起源于侧脑室脑室室下区（SVZ）的细胞，SVZ是新生儿至成人前脑中持续神经发生的部位，其中神经干细胞产生高度增殖的成神经细胞（NB），这些成神经细胞长距离迁移到正常大脑中的嗅球和脑损伤期间的病变部位。具体来说，我们将分析兴奋性毒性神经元损伤后的NB迁移，这与许多人类神经系统和神经退行性疾病高度相关。通过在不同发育阶段进行体内神经影像学实验，这些研究将提供关键的新信息，内源性神经干细胞介导修复的潜力的阶段依赖性差异，这应该有直接的影响，在不同年龄的脑损伤患者的反应。所有micro-MRI结果将通过组织学（包括免疫组织化学）进行验证，以确定NB迁移到损伤部位后的最终结局。我们也将开始分析特定生长因子对NSC和NB行为的影响。该项目的具体目标是：1）使用原位磁性细胞标记和体内micro-MRI，建立小鼠RMS中从新生儿到成年发育阶段NB细胞迁移的时间和空间特征; 2）分析脑损伤后NB细胞迁移的阶段依赖性变化，有和没有给予已知诱导NSC增殖的生长因子;以及3）在micro-MRI后获取的组织切片上使用免疫组织化学来确定磁性标记的NB迁移到嗅球和损伤部位后的最终分布和命运。在小鼠中进行成像研究的能力将使许多人脑疾病的基因工程小鼠模型中的NSC行为的重要未来研究成为可能，并使用这种大量的小鼠模型资源来测试旨在增强内源性NSC治疗效果的药物。 公共卫生相关性： 我们正在开发磁共振显微成像方法来标记小鼠大脑中的内源性神经干细胞（NSC），并跟踪它们在不同发育阶段的迁移，从新生儿到成年，以及在脑损伤小鼠中，有和没有给予生长因子以增强NSC的反应。兴奋性毒性神经元损伤模型与中风和许多人类神经发育和神经退行性疾病高度相关。在小鼠中进行成像研究的能力将使得能够在许多人脑疾病的基因工程小鼠模型中对NSC行为进行重要的未来研究，并使用这种大量的小鼠模型资源来测试设计用于增强内源性NSC的治疗效果的药物。

DESCRIPTION (provided by applicant): A promising therapeutic approach for brain injury and many neurological diseases is to harness the endogenous neural stem cells (NSCs) to replenish damaged neurons and glia. To study the response of NSCs to brain injury in mouse models, we are developing micro-MRI methods to label and track cells originating in the subventricular zone (SVZ) of the lateral ventricles, a site of persistent neurogenesis in the neonatal to adult forebrain in which NSCs generate highly proliferative neuroblasts (NBs) that migrate long distances to the olfactory bulb in the normal brain, and to lesion sites during brain injury. Specifically, we will analyze NB migration after excitotoxic neuronal injury, which is highly relevant to many human neurological and neuro-degenerative diseases. By performing in vivo neuroimaging experiments at different developmental stages, these studies will provide critical new information on the stage-dependent differences in the potential of endogenous NSCs to mediate repair, which should have direct implications for the responsiveness of patients experiencing brain injury at different ages. All of the micro-MRI results will be validated with histology, including immunohistochemistry to determine the final fates of the NBs after migration into injury sites. We will also begin to analyze the effects of specific growth factors on NSC and NB behavior. The specific aims of the project are: 1) to establish the temporal and spatial characteristics of NB cell migration in the mouse RMS from neonatal to adult stages of development, using in situ magnetic cell labeling and in vivo micro-MRI; 2) to analyze stage-dependent changes in NB cell migration after brain injury, with and without administration of growth factors known to induce NSC proliferation; and 3) to determine the final distributions and fates of the magnetically labeled NBs after migration into the olfactory bulb and injury sites, using immunohistochemistry on histological sections taken after micro-MRI. The ability to perform the imaging studies in mice will enable important future studies of NSC behaviors in genetically-engineered mouse models of many human brain diseases, and to use this vast resource of mouse models for testing drugs designed to enhance the therapeutic effects of the endogenous NSCs. PUBLIC HEALTH RELEVANCE: We are developing magnetic resonance micro-imaging approaches to label endogenous neural stem cells (NSCs) in the mouse brain, and to track their migrations at different developmental stages, from neonatal to adult, as well as in mice with brain injury, with and without administration of growth factors to enhance the response of the NSCs. The excitotoxic neuronal injury model is highly relevant to stroke and many human neurodevelopmental and neurodegenerative diseases. The ability to perform the imaging studies in mice will enable important future studies of NSC behaviors in genetically- engineered mouse models of many human brain diseases, and to use this vast resource of mouse models for testing drugs designed to enhance the therapeutic effects of the endogenous NSCs.