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是治疗脑损伤和许多神经系统疾病的一种很有前途的方法。为了在小鼠模型中研究NSCs对脑损伤的反应，我们正在开发微mri方法来标记和跟踪起源于侧脑室室下区（SVZ）的细胞，侧脑室是新生儿到成人前脑持续神经发生的部位，其中NSCs产生高度增殖的神经母细胞（NBs），这些神经母细胞可以长距离迁移到正常大脑的嗅球，以及脑损伤期间的病变部位。具体来说，我们将分析NB在兴奋性毒性神经元损伤后的迁移，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，这些研究将为内源性NSCs介导修复潜能的阶段依赖性差异提供重要的新信息，这将对不同年龄脑损伤患者的反应性产生直接影响。所有的微mri结果将与组织学进行验证，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)利用原位磁细胞标记和体内微mri技术，建立小鼠RMS中NB细胞从新生儿到成年发育阶段迁移的时空特征；2)分析脑损伤后NB细胞迁移的阶段依赖性变化，是否给予已知的诱导NSC增殖的生长因子；3)利用显微mri后的组织切片免疫组化技术，确定磁性标记的NBs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在许多人类脑部疾病的基因工程小鼠模型中研究NSC行为成为可能，并利用这一巨大的小鼠模型资源来测试旨在增强内源性NSCs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.