Developing MPI for Non-Invasive and Quantitative Imaging of Stem Cells

描述（由申请人提供）：细胞迁移，运输和归巢的非侵入性成像是一个新兴的新领域，可以为我们提供更深入地了解细胞组织相互作用的动力学，以及为使用干细胞的新疗法的开发提供指导。毫无疑问，细胞治疗领域最终将成为治疗或可能治愈各种神经退行性疾病的重要领域。因此，进一步发展可用于临床的敏感、非侵入性成像技术显然是有必要的。我们建议发展磁颗粒成像（MPI）作为干细胞成像的新技术。这种成像方式是基于已经用于MRI细胞跟踪的小型超顺磁示踪剂的非线性磁化曲线，但该技术本身与MRI无关。原则上，MPI比MRI有几个优点：a)灵敏度高1000倍；B)绝对量化磁性示踪剂和细胞数量的能力；c)“热点”解释，不存在MRI中混杂的内源性背景信号；d)由于出血或创伤性损伤而没有模糊的对比。我们有初步的数据表明，磁性标记的细胞可以在体外低浓度下用MPI原型仪器检测到，并且可以直接定量细胞数量和铁含量。在优化不同颗粒的标记程序后，MPI将在大脑中动脉闭塞的局灶性短暂性缺血大鼠模型中进一步进行体内研究。不同剂量的间充质干细胞和神经干细胞将被注入动脉内或静脉内。缺血性脑卒中的发展将通过各种MRI技术进行监测，包括灌注成像、扩散加权成像和pH成像。使用四层行为评分系统评估给药干细胞的治疗效果。MPI测定的缺血性病变中靶向和局部细胞的总量将与病变体积和行为评分相关。虽然这一建议可能被视为高风险，但我们相信，为了成功开发用于中风干细胞治疗的细胞MPI，所有必要的因素都已到位。通过利用MPI更好地了解大脑和其他组织中细胞在体内（选择性）归巢和（非选择性）捕获的动态过程，我们的目标是优化干细胞来源、给药途径和细胞注射剂量，最终提高干细胞治疗中风患者的疗效。公共卫生相关性：干细胞有可能改善甚至治愈神经退行性疾病，如中风。我们的目标是开发一种新的成像技术，使用磁性颗粒来可视化大脑中移植的干细胞。如果这项新技术开发成功，它将帮助我们更好地了解细胞进入大脑和身体其他部位的确切位置，这将有助于将这些干细胞引入患者体内。

DESCRIPTION (provided by applicant): Non-invasive imaging of cell migration, trafficking, and homing is an emerging new field that can provide us with a deeper insight into the dynamics of cell-tissue interactions, as well as provide guidance for the development of novel therapies using stem cells. There is little question that the field of cellular therapeutics will eventually become important to treat, or possibly cure, a variety of neurodegenerative diseases. Thus, further development of sensitive, non-invasive imaging techniques that can be applied clinically is clearly warranted. We propose to develop magnetic particle imaging (MPI) as a novel technique for imaging of stem cells. This imaging modality is based on the non-linear magnetization curve of small superparamagnetic tracers already used with MRI cell tracking, but the technique itself is not related to MRI. In principle, MPI has several advantages over MRI: a) a 1000-fold higher sensitivity; b) the ability to absolutely quantify the amount of magnetic tracers and cells; c) "hot spot" interpretation without the confounding endogenous background signal present in MRI; and d) the absence of obscuring contrast from hemorrhage or traumatic injury. We have preliminary data that magnetically labeled cells can be detected in vitro at low concentrations with a prototype MPI instrument, and that there is a straightforward quantification of cell number and iron content. Following the optimization of labeling procedures with different particles, MPI will be further investigated in vivo in a rat model of focal transient ischemia using middle cerebral artery occlusion. Different doses of mesenchymal and neural stem cells will be infused either intra-arterially or intravenously. The evolution of ischemic stroke will be monitored with various MRI techniques, including perfusion imaging, diffusion weighted imaging, and pH imaging. The therapeutic efficacy of administered stem cells will be assessed using a four-tier behavioral scoring system. The total amount of targeted and localized cells in the ischemic lesion, as determined by MPI, will be correlated with lesion volume and behavioral scores. While this proposal may be viewed as high risk, we believe that all necessary components are in place in order to successfully develop cellular MPI for stem cell therapy of stroke. By using MPI to obtain a better insight in the dynamic processes that govern the in vivo (selective) homing and (non-selective) trapping of cells in the brain and other tissues, we aim to optimize the source of stem cells, administration route, and dose of cell injection, which may ultimately enhance the therapeutic efficacy of stem cell treatment in stroke patients. PUBLIC HEALTH RELEVANCE: Stem cells have the potential to ameliorate or perhaps even cure neurodegenerative diseases such as stroke. We aim to develop a new imaging technique that uses magnetic particles for visualizing transplanted stem cells in the brain. If this new technique is developed successfully, it will help us to understand much better where the cells exactly go into the brain and elsewhere in the body, which will facilitate introducing these stem cells into patients.