In vivo MR Evaluation of Cell Therapy for Stroke

描述(申请人提供)：骨髓基质细胞(MSCs)治疗中风显著改善实验性中风患者的功能恢复。然而，关于移植的MSCs迁移的时间和空间分布以及这些细胞对宿主脑组织导致功能恢复的影响，人们知之甚少。我们建议开发无创的体内磁共振(MR)方法来追踪移植的MSCs并研究它们对宿主大脑的影响。在具体目标1中，我们将首先优化磁性造影剂标记和体内三维磁共振(MRI)监测宿主脑内移植的MSCs的方法学。然后，使用优化的方法，我们将检查不同的移植途径(静脉和脑池内)对中风患者大脑中移植细胞的存活、迁移和分布模式的影响。在具体目标2中，移植的MSCs对卒中后宿主脑血管生成和功能恢复的动态影响将通过MR无创测量，神经学结果将通过一系列行为测试来测量。将在同一动物身上分析MR测量的变化与动态功能改善之间的相关性。此外，将使用三维激光扫描共聚焦显微镜结合免疫组织化学来验证骨髓间充质干细胞移植后血管生成的MR测量的变化。通过这些新的方法，我们期望非侵入性磁共振测量将同时检测移植细胞的迁移和分布以及这些细胞对宿主脑组织的影响，并且MR测量的变化将与神经功能相关。因此，MR有可能为开发成功的中风细胞疗法提供重要的无创性测量。在完成我们的研究后，我们希望证明MR示踪磁性标记细胞是研究卒中细胞治疗的一种有效的新技术，这将导致细胞移植方案的优化和卒中治疗的改善。

DESCRIPTION (provided by applicant): Treatment of stroke with bone marrow stromal cells (MSCs) significantly improves functional recovery in experimental stroke. However, little is known about temporal and spatial profiles of migration of transplanted MSCs and the effects of these cells on host cerebral tissue leading to functional recovery. We propose to develop noninvasive in vivo magnetic resonance (MR) methodology for tracking transplanted MSCs and investigating their effects on the host brain. In Specific Aim 1, we will first optimize methodology for magnetic contrast agent labeling and in vivo three dimensional magnetic resonance (MRI) monitoring of transplanted MSCs in the host brain. Using the optimized methodology, we will then examine the effects of different routes (intravenous vs intracisternal) of transplantation on survival, migration, and distribution patterns of transplanted cells in brain subjected to stroke. In Specific Aim 2, dynamic effects of transplanted MSCs on the host brain angiogenesis and functional recovery after stroke will be noninvasively measured by means of MR. Neurological outcome will be measured using a battery of behavioral tests. Correlation between changes in MR measurements and dynamic functional improvements will be analyzed in the same animal. In addition, changes in MR measurements of angiogenesis resulting from MSC transplantation will be verified using three dimensional laser scanning confocal microscopy in combination with immuno-histochemistry. With these novel approaches, we expect that noninvasive MR measurements will simultaneously detect the migration and distribution of transplanted cells and the effects of these cells on the host brain tissue, and that changes in MR measurements will correlate to neurological function. Therefore, MR could potentially provide important noninvasive measurements for developing a successful cell therapy for stroke. After completing our studies, we expect to demonstrate that MR tracking magnetic labeled cells is a valid new technique for studying cell therapy for stroke, which will lead to optimization of cell transplantation protocols and improved management of stroke.