MRI Tracking of Stem Cell Migration During Brain Injury

描述（由申请人提供）：脑损伤和许多神经系统疾病的一种有前景的治疗方法是利用内源性神经干细胞（NSC）来补充受损的神经元和神经胶质细胞。为了研究小鼠模型中 NSC 对脑损伤的反应，我们正在开发微型 MRI 方法来标记和跟踪源自侧脑室室下区 (SVZ) 的细胞，SVZ 是新生儿到成人前脑中持续神经发生的部位，其中 NSC 产生高度增殖的神经母细胞 (NB)，这些细胞长距离迁移到正常大脑中的嗅球，并在脑损伤期间迁移到病变部位。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实验，这些研究将提供有关内源性神经干细胞介导修复潜力的阶段依赖性差异的重要新信息，这应该对不同年龄经历脑损伤的患者的反应能力产生直接影响。所有微型 MRI 结果都将通过组织学（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命运。我们还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）利用原位磁性细胞标记和体内微MRI，建立小鼠RMS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，无论是否施用已知诱导 NSC 增殖的生长因子； 3）通过对显微 MRI 后采集的组织切片进行免疫组织化学分析，确定磁性标记的 NB 在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未来对许多人脑疾病的基因工程小鼠模型中的 NSC 行为进行重要研究成为可能，并利用这一庞大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。 公共健康相关性：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（从新生儿到成年）以及脑损伤小鼠中的迁移，无论是否施用生长因子以增强 NSC 的反应。兴奋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未来对许多人脑疾病的基因工程小鼠模型中的 NSC 行为进行重要研究成为可能，并利用这一庞大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。

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.