MRI Tracking of Stem Cell Migration During Brain Injury

描述(申请人提供)：利用内源性神经干细胞(NSCs)来补充受损的神经元和神经胶质细胞是治疗脑损伤和许多神经疾病的一种有前途的方法。为了在小鼠模型中研究神经干细胞对脑损伤的反应，我们正在开发微型MRI方法来标记和跟踪起源于侧脑室下区(SVZ)的细胞，侧脑室下区是新生到成人前脑中持续神经发生的位置，在那里NSCs产生高度增殖的神经母细胞(NBS)，在正常脑中迁移到嗅球，并在脑损伤期间迁移到病变位置。具体地说，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成像实验，这些研究将提供关于内源性神经干细胞介导修复潜力的阶段依赖差异的关键新信息，这应该对不同年龄经历脑损伤的患者的反应性有直接影响。所有的显微核磁共振结果将通过组织学进行验证，包括免疫组织化学，以确定NBS迁移到损伤部位后的最终命运。我们还将开始分析特定的生长因素对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Micro-MRI技术，建立小鼠RMS从新生到成年发育阶段NB细胞迁移的时空特征；2)分析脑损伤后NB细胞迁移随时间的变化；以及3)利用Micro-MRI后获取的组织切片进行免疫组织化学染色，确定NBS在脑损伤后迁移到嗅球和损伤部位后的最终分布和命运。在小鼠身上进行成像研究的能力将使未来能够在许多人类大脑疾病的基因工程小鼠模型中对NSC行为进行重要研究，并利用这一巨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。 与公众健康相关：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(NSCs)，并跟踪它们在不同发育阶段的迁移，从新生儿到成年，以及在有脑损伤的小鼠中，在注射和不注射生长因子的情况下，以增强NSCs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密切相关。在小鼠身上进行成像研究的能力将使未来能够在许多人类大脑疾病的基因工程小鼠模型中对NSC行为进行重要研究，并利用这一巨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.