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，可以为我们提供对细胞-组织相互作用动力学的更深入了解，并为开发使用干细胞的新型疗法提供指导。毫无疑问，细胞治疗学领域最终将成为治疗或治愈各种神经退行性疾病的重要领域。因此，进一步发展敏感的，非侵入性的成像技术，可以应用于临床显然是必要的。我们建议开发磁粒子成像（MPI）作为一种新的干细胞成像技术。这种成像模式是基于已经与MRI细胞跟踪一起使用的小型超顺磁性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具有优于MRI的几个优点：a）1000倍高的灵敏度; B）绝对量化磁性示踪剂和细胞的量的能力; c）“热点”解释，而不存在MRI中的混杂内源性背景信号;以及d）不存在来自出血或创伤性损伤的模糊对比。我们有初步的数据，磁性标记的细胞可以在体外检测到低浓度的原型MPI仪器，并有一个简单的量化细胞数量和铁含量。在用不同颗粒优化标记程序后，将在使用大脑中动脉闭塞的局灶性短暂缺血大鼠模型中进一步研究MPI。不同剂量的间充质和神经干细胞将通过动脉内或静脉内输注。将采用各种MRI技术监测缺血性卒中的进展，包括灌注成像、弥散加权成像和pH成像。将使用四级行为评分系统评估施用的干细胞的治疗功效。通过MPI确定的缺血性病变中靶向和定位细胞的总量将与病变体积和行为评分相关。虽然这项建议可能被视为高风险，但我们认为，所有必要的组成部分都已到位，以便成功开发用于中风干细胞治疗的细胞MPI。通过使用MPI来更好地了解控制脑和其他组织中细胞的体内（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的来源，给药途径和细胞注射剂量，这可能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，使用磁性粒子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.