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

用于中风治疗的预处理人间充质干细胞的 MR 分析

• 批准号: 9470503
• 负责人: Samuel Colles Grant
• 金额: $ 36.09万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9470503
• 关键词: Acute; Address; Adipose tissue; Adult; Agitation; Alteplase; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Behavioral; Biochemical; Biodistribution; Biomedical Engineering; Bioreactors; Bone Marrow; Bone Marrow Stem Cell; Brain; CXCR4 gene; Cause of Death; Cell Culture Techniques; Cell Proliferation; Cell Therapy; Cells; Chronic Phase; Clinical; Early Intervention; Effectiveness; Engraftment; Environment; Equilibrium; FDA approved; Fibrinolytic Agents; Genetic; Germ Cells; Glycolysis; Goals; Homeostasis; Homing; Hospitals; Human; Hypoxia; Image; Image Analysis; Immune response; Immunohistochemistry; Implant; In Situ; In Vitro; Individual; Injection of therapeutic agent; Intra-Arterial Injections; Ischemia; Ischemic Stroke; Knowledge; Label; Lesion; Magnetic Resonance Imaging; Mesenchymal Stem Cells; Methods; Modification; Monitor; Nerve Degeneration; Neurologic; Osmoregulation; Outcome; Oxygen; Patients; Perfusion; Pharmaceutical Preparations; Phase; Play; Population; RNA Interference; Recovery; Recovery of Function; Recruitment Activity; Recurrence; Relaxation; Research Personnel; Resistance; Resolution; Risk; Role; Sensitivity and Specificity; Sodium; Source; Spectrum Analysis; Stem cell transplant; Stem cells; Stress; Stroke; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Transplantation; Treatment Efficacy; Up-Regulation; acute stroke; adult stem cell; angiogenesis; base; cell behavior; cell motility; clinical application; clinical translation; conditioning; cytokine; density; design; disability; experience; experimental study; improved; in vivo; insight; knock-down; magnetic field; migration; nerve stem cell; neurogenesis; non-genetic; novel; novel strategies; pre-clinical; preconditioning; regenerative; relating to nervous system; repaired; response; restoration; spectroscopic imaging; stroke intervention; stroke recovery; stroke therapy; stroke treatment; subventricular zone; success; therapy outcome

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.

项目摘要 在美国，中风是死亡的第三大主要原因，是严重残疾的主要原因， 每年有700,000个人经历缺血性发作。组织纤溶酶原激活剂，唯一的FDA 批准的中风的溶栓药，必须在初始缺血后的短时间内在短时间内注入 有限的好处和结果。使用成年干细胞（例如人间充质干）的中风疗法 骨髓和脂肪组织源的细胞（HMSC）已成为减少的有前途的途径 并通过促进组织保护和修复而导致中风导致的反向神经变性。项目 试图（a）研究其归寄养和植入的HMSC的体内命运和机制 使用高场磁共振成像（MRI）和光谱法的治疗益处 （MRS）和（b）定义保留HMSC治疗的扩展和预先调节文化环境 效力。该项目的假设是HMSC扩展条件会影响中风治疗的功效 尽管低氧诱导因素以及这些影响可以在时间过程中进行监测并进一步优化 由In Vivo High Field MRI和MRS收集的有关功能恢复的信息。该项目建立在 互补的专业知识和初步结果在中风动物中对HMSC命运的高场MRI分析作为 以及用于HMSC扩展的生物反应器系统。该项目将调查迁移和植入 通过MR技术在中风病变中培养扩展的HMSC，并描述了缺氧前的影响 在体内命运的HMSC上的调节和聚集。该项目还将评估HMSC和 内源性神经源性构成及其在中风病变恢复中的协同作用。这些努力的目标将 确定在中风恢复期间扩大了培养的时间注射，并确定 HMSC治疗的功效超出了溶栓药的当前窗口。另外，作为一种 翻译发现，该项目调查了生物反应器条件，使可伸缩以增加 人类患者的可用性并影响治疗功效。该项目的成功将扩大 对体内HMSC命运的知识受到预活化影响，确定的机制和范围 HMSC在中风恢复中的影响，并建立可扩展的生物反应器策略以进行临床翻译。 关联 缺血性发作后必须迅速采用当前的溶栓剂 但是5％的中风患者。 HMSC在此急性窗口外促进中风病变恢复，但最终 临床应用需要深入了解机制和生物分布以及可用性 可移植的细胞种群。该项目利用一套独特的实验，旨在提供 对生物反应器的疗效的机械洞察力扩展和预先调节的HMSC对中风治疗。