MR Tracking of Magnetically Labeled Stem Cells in CNS

中枢神经系统中磁标记干细胞的 MR 追踪

• 批准号: 6754952
• 负责人: Jeff W. Bulte
• 金额: $ 5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754952
• 关键词: Krabbe's disease; Parkinson's disease; Sindbis virus; bioimaging /biomedical imaging; bone marrow; cell line; cell migration; central nervous system; degenerative motor system disease; disease /disorder model; embryonic stem cell; gene targeting; genetically modified animals; iron oxide; laboratory mouse; laboratory rat; magnetic resonance imaging; magnetism; myelination; myelinopathy; nervous system disorder therapy; neural degeneration; nonhuman therapy evaluation; radiotracer; stem cell transplantation

DESCRIPTION (provided by applicant):Stem cells have the potential to treat and possibly cure a variety of disorders, particularly those of the central nervous system (CNS). To develop successful clinical therapies, the fate of these cells after grafting must be monitored in a noninvasive manner. Currently, there is a need to develop in vivo means to track transplanted cells to determine their survival and migration patterns. By attaching a magnetic tag to stem cells, we propose to follow their biodistribution in vivo using MR imaging. We hypothesize that MR monitoring of the extent of cell migration, including the local distribution within the CNS, will allow for optimization of stem cell transplantation protocols, and that the same strategy may eventually be pursued in humans. Specifically, we will label bone marrow stem cells and neural stem cells obtained from mouse embryonic stem (ES) cell lines. Our first aim is to optimize the magnetic labeling procedure using superparamagnetic iron oxides that are coated with a transfection agent. Following magnetic tagging, we will then graft labeled cells into the CNS or inject cells systemically into the following four animal models of neurodegenerative disease: a) Long Evans shaker rat model of dysmyelination (aim 2); b) Twitcher mouse model of globoid cell leukodystrophy (aim 3); c) Sindbis virus rat model of lower motor neuron disease (aim 4); and d) mouse model of Parkinson's disease (aim 5). These models are believed to represent human CNS diseases that are likely candidates for future stem cell therapy. Using serial MR imaging of the same animal over time, unique information on the spatial temporal dynamics of cell migration can be obtained. Specifically, we aim to correlate the obtained MR contrast images with conventional histopathologic labeling and staining techniques for each differentiated cell type, to determine the extent of new myelination or dopaminergic neuron formation and the potential improvement in animal behavior. Upon the completion of our studies, we expect to demonstrate that MR tracking of magnetically labeled stem cells is a valid new technology for studying stem cell based therapies in the CNS, setting the stage for applying this technique in a clinical setting.

描述（由申请人提供）：干细胞具有治疗和可能治愈多种疾病的潜力，特别是中枢神经系统（CNS）的疾病。为了开发成功的临床疗法，必须以非侵入性方式监测移植后这些细胞的命运。目前，需要开发体内方法来追踪移植细胞以确定其存活和迁移模式。通过将磁性标签附着到干细胞上，我们建议使用磁共振成像来跟踪它们在体内的生物分布。我们假设，磁共振监测细胞迁移的程度，包括中枢神经系统内的局部分布，将允许优化干细胞移植方案，并且最终可能在人类中采用相同的策略。具体来说，我们将标记从小鼠胚胎干（ES）细胞系获得的骨髓干细胞和神经干细胞。我们的首要目标是使用涂有转染剂的超顺磁性氧化铁来优化磁性标记程序。磁标记后，我们将标记的细胞移植到中枢神经系统或将细胞全身注射到以下四种神经退行性疾病动物模型中： a) 髓鞘形成障碍的 Long Evans shaker 大鼠模型（目标 2）； b) 球状细胞脑白质营养不良的 Twitcher 小鼠模型（目标 3）； c)辛德比斯病毒下运动神经元疾病大鼠模型（目标4）； d) 帕金森病小鼠模型（目标 5）。这些模型被认为代表了人类中枢神经系统疾病，这些疾病可能是未来干细胞疗法的候选者。使用同一动物随时间变化的连续磁共振成像，可以获得有关细胞迁移的时空动态的独特信息。具体来说，我们的目标是将获得的 MR 对比图像与每种分化细胞类型的常规组织病理学标记和染色技术相关联，以确定新髓鞘形成或多巴胺能神经元形成的程度以及动物行为的潜在改善。研究完成后，我们希望证明磁性标记干细胞的 MR 追踪是研究中枢神经系统干细胞疗法的有效新技术，为在临床环境中应用该技术奠定基础。