MSCs Induce Brain Plasticity via tPA

间充质干细胞通过 tPA 诱导大脑可塑性

• 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
• 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

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（由应用程序提供）：基于细胞的疗法在减少与中风相关的神经系统防御方面表现出了巨大的希望。这些疗法中最有效的一种是骨髓基质细胞（MSC），已被证明是高度神经培训的。在此应用中，我们将研究MSC产生这种神经疏松作用的机制。我们的初步数据强烈表明，MSC治疗中风会促进大脑的神经落重塑。我们提出，当中风后给药时，MSC会激活实质细胞内组织纤溶酶原激活剂（TPA），而TPA介导神经蛋白的重塑，从而改善了神经学功能。因此，测试了以下三个假设：假设1：a）MSC会增加实质细胞中的TPA活性； b）TPA活性增加会增加神经蛋白的重塑； c）神经蛋白重塑的增加有助于改善中风后功能结果。假设2：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通过SHH信号通路下调TGF- - 1/PAI-1，从而增加了TPA活性。假说3：MSCS的TPA活性通过纤溶酶依赖性蛋白水解裂解促进神经型神经型神经型促蛋白：促脑神经营养因子（Pro-NGF）对NGF，亲脑衍生的神经营养性因子（Pro-bdnf）对这些假设的疾病和疾病的相互作用，对这些假设的疾病的相互作用，中风后TPA活性，神经重塑和神经功能。我们的研究采用转基因的TPA - / - ，PLG - / - 小鼠以及我们实验室中的一系列新颖且已建立的实验技术。据我们所知，我们的工作是第一个研究TPA活性，作为扩增CNS外源细胞有益作用的关键统一因素。该项目是一种连贯且高度交织的努力，旨在阐明分子和细胞途径，通过基于细胞的疗法可以重塑受伤的大脑。我们的最终目标是描述中风恢复性治疗中基于细胞治疗的机械基础。我们的研究对所有神经系统疾病和损伤的治疗意义得到了证明。 公共卫生相关性：我们的研究将提供有关如何重塑受伤大脑的基本见解，并使用基于细胞的疗法改善神经功能。使用外源给予细胞的恢复性疗法不受狭窄的治疗窗口的限制，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，可能会导致基于果味的基于细胞的疗法治疗中风和神经损伤。