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: 10238759
• 负责人: Samuel Colles Grant
• 金额: $ 33.3万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238759
• 关键词: 3-Dimensional; Acute; Address; Adipose tissue; Adult; Agitation; Alteplase; Animals; Anti-Inflammatory Agents; Behavioral; Biochemical; Biodistribution; Biomedical Engineering; Bioreactors; Bone Marrow; Brain; CXCR4 gene; Cause of Death; Cell Culture Techniques; Cell Proliferation; Cell Therapy; Cell Transplantation; 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; Immune response; Immunohistochemistry; Implant; In Situ; In Vitro; Individual; Injections; 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; Recurrence; Relaxation; Research Personnel; Resistance; Resolution; Risk; Role; Sensitivity and Specificity; Sodium; Source; Spectrum Analysis; Stem cell transplant; Stress; Stroke; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Transplantation; Treatment Efficacy; Up-Regulation; acute stroke; adult stem cell; angiogenesis; base; bone marrow mesenchymal stem cell; 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; post stroke; pre-clinical; preconditioning; preservation; recruit; regenerative; relating to nervous system; repaired; response; restoration; spectroscopic imaging; stem cell expansion; stem cell fate; stem cell therapy; stem cells; stroke intervention; stroke patient; stroke recovery; stroke therapy; 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，中风是第三大死亡原因和严重残疾的主要原因， 每年有70万人经历缺血发作。组织纤溶酶原激活剂，唯一的FDA 批准的用于中风的溶栓药物，必须在初始缺血后的短时间内输注， 其益处和结果有限。使用成人干细胞如人间充质干细胞治疗中风 来自骨髓和脂肪组织来源的人间充质干细胞（hMSC）已成为一种有前途的途径，以减少 并通过促进组织保护和修复来逆转中风导致的神经变性。项目 目的是（a）研究植入的hMSC的体内命运和机制，这些是它们归巢的基础， 使用高场磁共振成像（MRI）和光谱学治疗中风的治疗益处 (MRS)和（B）确定保持hMSC治疗性的扩增和预处理培养环境 力量该项目的假设是hMSC扩增条件影响中风治疗的疗效 通过低氧诱导因素，这些影响可以监测并随着时间的推移进一步优化 通过体内高场MRI和MRS收集的关于功能恢复的信息。该项目是建立在 补充专业知识和高场MRI分析中风动物hMSC命运的初步结果， 以及用于hMSC扩增的生物反应器系统。该项目将调查 通过MR技术在卒中病变中培养扩增的hMSC，并描述缺氧预处理的影响。 调节和聚集对hMSC体内命运的影响。该项目还将评估hMSC和 内源性神经祖细胞及其在卒中损伤恢复中的作用。这些努力的目标将 确定在中风恢复期间实现培养扩增的hMSC的定时注射，并确定 hMSC治疗的疗效超出了目前溶栓药物的窗口。此外，作为一种手段， 翻译结果，该项目调查了生物反应器的条件，使可扩展的扩展，以增加 对人类患者的可用性并影响治疗功效。这个项目的成功将扩大 关于体内hMSC命运受预活化影响的知识，确定其机制和范围， 影响hMSC在中风恢复中的作用，并建立用于临床转化的可扩展生物反应器策略。 相关性 目前的溶栓药物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。 但只有5%的中风患者hMSC在急性期窗外促进卒中损伤恢复，但其最终 临床应用需要深入了解机制和生物分布以及 可移植的细胞群利用一套独特的实验，该项目旨在提供 对生物反应器扩增和预处理的hMSC用于中风治疗的功效的机械见解。

项目成果

Aggregation of Culture Expanded Human Mesenchymal Stem Cells in Microcarrier-based Bioreactor.

• DOI: 10.1016/j.bej.2017.12.011
• 发表时间: 2018-03-15
• 期刊: Biochemical engineering journal
• 影响因子: 3.9
• 作者: Yuan X;Tsai AC;Farrance I;Rowley J;Ma T
• 通讯作者: Ma T

Gut dysbiosis in stroke and its implications on Alzheimer's disease-like cognitive dysfunction.

• DOI: 10.1111/cns.13613
• 发表时间: 2021-05
• 期刊: CNS neuroscience & therapeutics
• 影响因子: 5.5
• 作者: Cho J;Park YJ;Gonzales-Portillo B;Saft M;Cozene B;Sadanandan N;Borlongan CV
• 通讯作者: Borlongan CV

LncRNAs Stand as Potent Biomarkers and Therapeutic Targets for Stroke.

LncRNA 是中风的有效生物标志物和治疗靶点

• DOI: 10.3389/fnagi.2020.594571
• 发表时间: 2020
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8
• 作者: Fan J;Saft M;Sadanandan N;Gonzales-Portillo B;Park YJ;Sanberg PR;Borlongan CV;Luo Y
• 通讯作者: Luo Y

Stem Cell Repair of the Microvascular Damage in Stroke.

• DOI: 10.3390/cells9092075
• 发表时间: 2020-09-11
• 期刊: Cells
• 影响因子: 6
• 作者: Saft M;Gonzales-Portillo B;Park YJ;Cozene B;Sadanandan N;Cho J;Garbuzova-Davis S;Borlongan CV
• 通讯作者: Borlongan CV

Mesenchymal Stem Cell-Induced Anti-Neuroinflammation Against Traumatic Brain Injury.

• DOI: 10.1177/09636897211035715
• 发表时间: 2021-01
• 期刊: Cell transplantation
• 影响因子: 3.3
• 作者: Cozene B;Sadanandan N;Farooq J;Kingsbury C;Park YJ;Wang ZJ;Moscatello A;Saft M;Cho J;Gonzales-Portillo B;Borlongan CV
• 通讯作者: Borlongan CV