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: 8104726
• 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/8104726
• 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; 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（由申请人提供）：基于细胞的疗法在减少与中风相关的神经功能缺损方面显示出巨大的前景。这些疗法中最有效的一种是骨髓基质细胞（MSC），已被证明具有高度的神经修复作用。在本申请中，我们将研究MSC产生这种神经修复作用的机制。我们的初步数据有力地表明，MSC治疗中风促进脑神经突起重塑。我们建议，当中风后，MSC激活组织纤溶酶原激活剂（tPA）的实质细胞内，和tPA介导的神经突起重塑，导致改善神经功能。因此，检验以下三个假设：假设1：a）MSC增加实质细胞中的tPA活性; B）增加的tPA活性增加神经突重塑; c）增加的神经突重塑有助于改善中风后的功能结果。假设二：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-β 1/派-1，从而增加tPA活性。假设三：由MSC增加的tPA活性通过纤溶酶依赖性的前神经营养因子的蛋白水解裂解促进神经突重塑：前神经生长因子（pro-NGF）至NGF，前脑源性神经营养因子（pro-BDNF）至BDNF这些假说剖析了外源性MSC和内源性实质细胞的相互作用及其对中风后tPA活性、神经突重塑和神经功能的影响。我们的研究采用了转基因tPA-/-，Plg-/-小鼠以及一系列新的和完善的实验技术在我们的实验室。据我们所知，我们的工作是第一次调查tPA活性作为一个关键的统一因素，以放大外源性细胞在中枢神经系统中的有益作用。该项目是一个连贯和高度交织的努力，以阐明分子和细胞途径，通过这些途径，受伤的大脑可以通过基于细胞的疗法进行重塑。我们的最终目标是阐明细胞疗法在中风恢复治疗中的机制基础。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。 公共卫生相关性：我们的研究将为如何使用基于细胞的治疗来重塑受损的大脑和改善神经功能提供重要的见解。使用外源性给予细胞的恢复性治疗不受狭窄治疗窗的限制，并且可以给予所有中风患者。我们的目标是确定这些给予的细胞如何与内源性脑细胞相互作用，这可能会使基于细胞的恢复性治疗中风和神经损伤的治疗取得成果。