MR Analysis of Pre-Conditioned Human Mesenchymal Stem Cells for Stroke Therapy

项目摘要 在美国，中风是第三大致死原因和严重残疾的主要原因，超过 每年有70万人经历一次脑缺血发作。组织纤溶酶原激活剂，唯一的FDA 经批准的治疗中风的溶栓药物，必须在最初缺血后的短时间内输注，并 效益和结果有限。人骨髓间充质干细胞等成体干细胞治疗中风 来自骨髓和脂肪组织来源的细胞(HMSC)已经成为一种有希望的途径来减少 并通过促进组织保护和修复来逆转中风引起的神经退化。该项目 寻求(A)研究植入的人骨髓间充质干细胞在体内的命运和机制，这是其归巢和 高场磁共振成像和光谱学在卒中治疗中的疗效 (MRS)和(B)定义保存hMSC治疗性的扩增和预调节培养环境 威力。该项目的假设是hMSC的扩张条件会影响中风治疗的疗效 通过低氧诱导因素，这些影响可以被监测并随着时间的推移而进一步优化 通过体内高场MRI和MRS收集有关功能恢复的信息。这个项目是建立在 高场MRI分析卒中动物AS中hMSC命运的互补技术和初步结果 以及用于hMSC扩张的生物反应器系统。该项目将调查移民和嫁接 用磁共振技术在卒中病变内培养扩增的hMSC，并描绘低氧预适应的影响 条件和聚集对人骨髓间充质干细胞体内命运的影响。该项目还将评估hMSC和HMSC的互动 内源性神经前体细胞及其在卒中损伤修复中的协同作用。这些努力的目标将是 目的：确定卒中恢复期间能否实现培养扩增的hMSC的定时注射，并确定 目前溶栓药物窗口之外的hMSC治疗的疗效。此外，作为一种手段 翻译发现，该项目调查了生物反应器的条件，使可伸缩的扩展增加 对人类患者的可用性和影响治疗效果。这个项目的成功将会扩大。 了解预活化对体内人骨髓间充质干细胞命运的影响，确定其机制和范围 对hMSC在中风康复中的作用的影响，并建立可扩展的生物反应器策略用于临床翻译。 相关性 目前的溶栓剂必须在缺血发作后迅速使用，限制了它们在所有患者中的有效性 但5%的中风患者。HMSC促进卒中病变在这个急性窗口之外的恢复，但他们的最终 临床应用需要对机制和生物分布的深入了解以及可获得性 一个可移植的细胞群体。利用一套独特的实验，该项目旨在提供 对生物反应器扩大和预调节的hMSC治疗中风的有效性的机械洞察。

Project Summary In the US, stroke is the third leading cause of death and primary cause of severe disability, with over 700,000 individuals experiencing an ischemic episode each year. Tissue plasminogen activator, the only FDA approved thrombolytic drug for stroke, must be infused within a short period following the initial ischemia and has limited benefits and outcomes. Stroke therapy using adult stem cells such as human mesenchymal stem cells (hMSC) from bone marrow and adipose tissue sources has emerged as a promising avenue to reduce and reverse neurodegeneration resulting from stroke by promoting tissue protection and repair. The project seeks to (a) investigate the in vivo fate and mechanisms of implanted hMSC that underlie their homing and therapeutic benefits in stroke treatment using high field magnetic resonance imaging (MRI) and spectroscopy (MRS) and (b) define expansion and pre-conditioning culture environments that preserve hMSC therapeutic potency. The project's hypothesis is that hMSC expansion conditions impact efficacy in stroke treatment though hypoxic induction factors, and these impacts can be monitored and further optimized with time course information gathered by in vivo high field MRI and MRS about functional recovery. The project is built upon complementary expertise and preliminary results in high field MRI analysis of hMSC fate in stroked animals as well as bioreactor systems for hMSC expansion. The project will investigate the migration and engraftment of culture-expanded hMSC within stroke lesions by MR techniques and delineate the impact of hypoxic pre- conditioning and aggregation on hMSC in vivo fate. The project also will evaluate the interactions of hMSC and endogenous neuroprogenitors and their synergist role in stroke lesion recovery. The goal of these efforts will be to determine achieve timed injections of culture expanded hMSC during stroke recovery and determine the efficacy of hMSC therapy beyond the current window of thrombolytic drugs. Additionally, as a means of translating findings, the project investigates bioreactor conditions that enable scalable expansion to increase availability to human patients and impact therapeutic efficacy. The success of this project will expand knowledge about in vivo hMSC fate as influenced by pre-activation, identify the mechanisms and range of impacts for hMSC action in stroke recovery, and establish a scalable bioreactor strategy for clinical translation. Relevance Current thrombolytic agents must be employed quickly after ischemic onset, limiting their effectiveness in all but 5% of stroke patients. hMSC promote stroke lesion recovery outside this acute window, but their eventual clinical application requires in-depth knowledge of mechanisms and biodistribution as well as the availability of a transplantable cell population. Utilizing a unique set of experiments, the project is designed to provide mechanistic insights into the efficacy of bioreactor expanded and pre-conditioned hMSC for stroke treatment.