MSCs Induce Brain Plasticity via tPA

间充质干细胞通过 tPA 诱导大脑可塑性

基本信息

批准号：
8248705
负责人：
MICHAEL CHOPP
金额：
$ 30.03万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8248705
关键词：
Address Affect Aftercare Alteplase Astrocytes Bone Marrow Brain Brain-Derived Neurotrophic Factor Cell Therapy Cells Data Endothelial Cells Erinaceidae Goals In Vitro Knock-out Laboratories Marrow Mediating Modeling Molecular Mus Nerve Growth Factors Nervous System Physiology Nervous System Trauma Neuraxis Neurites Neuroglia Neurologic Neurons Pathway interactions Patients Plasmin Plasminogen Plasminogen Activator Plasminogen Activator Inhibitor 1 Play Production Proteolysis Recovery of Function Role Sonic Hedgehog Pathway Stroke Stromal Cells Synapses System Techniques Testing Therapeutic Wild Type Mouse Work base brain cell brain remodeling brain tissue design effective therapy functional improvement functional outcomes human TGFB1 protein improved in vivo injured insight nerve injury nervous system disorder neurological recovery neurorestoration neurotrophic factor novel public health relevance research study restorative treatment smoothened signaling pathway

项目摘要

DESCRIPTION (provided by applicant): Cell-based therapies have shown enormous promise in reducing neurological deficits associated with stroke. One of the most effective of these therapies is bone marrow stromal cells (MSCs), that has been demonstrated to be highly neurorestorative. In this application, we will investigate the mechanisms by which MSCs produce this neurorestorative effect. Our preliminary data strongly indicate that MSC treatment of stroke promotes neurite remodeling of brain. We propose that when administered after stroke, MSCs activate tissue plasminogen activator (tPA) within parenchymal cells, and tPA mediates neurite remodeling leading to improvement in neurological function. Therefore, the following three hypotheses are tested: Hypothesis 1: a) MSCs increase tPA activity in parenchymal cells; b) Increased tPA activity increases neurite remodeling; c) Increased neurite remodeling contributes to improvement of functional outcome after stroke. Hypothesis 2: a) MSCs up-regulate tPA activity in astrocytes, neurons and endothelial cells via the Shh signaling pathway; b) MSCs down-regulate TGF-¿1/PAI-1 via the Shh signaling pathway and thereby increase tPA activity. Hypothesis 3: tPA activity increased by MSCs promotes neurite remodeling via plasmin-dependent proteolytic cleavage of pro-neurotrophins: pro-nerve growth factor (pro-NGF) to NGF, pro-brain derived neurotrophic factor (pro-BDNF) to BDNF These hypotheses dissect the interactions of exogenous MSCs and endogenous parenchymal cells and their affect on tPA activity, neurite remodeling and neurological function after stroke. Our studies employ genetically modified tPA-/-, Plg-/-mice as well as an array of novel and well-established experimental techniques in our laboratory. To our knowledge, our work is the first to investigate tPA activity as a key unifying factor to amplify beneficial actions of exogenous cells in the CNS. This project is a coherent and highly interwoven effort to elucidate the molecular and cellular pathways by which injured brain can be remodeled by cell-based therapies. Our ultimate goal is to delineate the mechanistic underpinnings of cell-based therapy in the restorative treatment of stroke. The therapeutic implications of our studies for all neurological disease and injury are evident. PUBLIC HEALTH RELEVANCE: Our study will provide essential insight into how the injured brain is remodeled and neurological function improved using a cell-based therapy. Restorative therapy using exogenously administered cells is not limited by a narrow therapeutic window and can be administered to all stroke patients. Our goal to identify how these administered cells interact with the endogenous brain cells will likely bring to fruition restorative cell-based therapy for the treatment of stroke and neural injury.

描述（由申请人提供）：基于细胞的疗法在减少与中风相关的神经缺陷方面显示出巨大的前景，其中最有效的疗法之一是骨髓基质细胞（MSC），其已被证明具有高度的神经恢复作用。在本申请中，我们将研究 MSC 产生这种神经恢复作用的机制。我们的初步数据强烈表明，MSC 治疗中风可促进大脑神经突重塑。我们建议，在中风后给药时，MSC 会激活。实质细胞内的组织纤溶酶原激活剂（tPA），并且 tPA 介导神经突重塑，从而改善神经功能。因此，测试了以下三个假设：假设 1：a) MSC 增加实质细胞中的 tPA 活性；b) tPA 活性增加。神经突重塑；c) 神经突重塑的增加有助于改善中风后的功能结果：a) MSC。通过 Shh 信号通路上调星形胶质细胞、神经元和内皮细胞中的 tPA 活性 b) MSC 下调 TGF-¿ 1/PAI-1 通过 Shh 信号通路增加 tPA 活性，从而增加 tPA 活性。假设 3：MSC 增加的 tPA 活性通过纤溶酶依赖性前神经营养蛋白的蛋白水解裂解促进神经突重塑：前神经生长因子 (pro-NGF) 转化为 NGF。，前脑源性神经营养因子（pro-BDNF）到 BDNF 这些假设剖析了外源性 MSC 和内源性的相互作用我们的研究采用了转基因 tPA-/-、Plg-/- 小鼠以及我们实验室的一系列新颖且成熟的实验技术。据我们所知，我们的工作是第一个研究 tPA 活性作为放大中枢神经系统中外源细胞有益作用的关键统一因素的工作，该项目是一项连贯且高度交织的努力，旨在阐明分子和功能。我们的最终目标是阐明细胞疗法在中风恢复性治疗中的机制基础，我们的研究对所有神经系统疾病和损伤的治疗意义是显而易见的。。公共健康相关性：我们的研究将提供关于如何使用基于细胞的疗法重塑受损大脑和改善神经功能的重要见解。使用外源性细胞的恢复疗法不受狭窄治疗窗的限制，并且可以对所有中风患者进行。我们的目标是确定这些施用的细胞如何与内源性脑细胞相互作用，这可能会为治疗中风和神经损伤的基于细胞的恢复疗法带来成果。