Promotion of neurovascular remodeling through mitochondria transfer after stroke

中风后通过线粒体转移促进神经血管重塑

• 批准号: 9009202
• 负责人: Kazuhide Hayakawa
• 金额: $ 37.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9009202
• 关键词: Astrocytes; Biological Markers; Blood Vessels; Brain; Brain Injuries; Calcium; Cells; Central Nervous System Diseases; Cicatrix; Coculture Techniques; Confocal Microscopy; Culture Media; Cyclic ADP-Ribose; Data; Electron Microscopy; Endothelial Cells; Endothelium; Etiology; Glucose; HMGB1 gene; Heat shock proteins; Human; Image; In Vitro; Inflammation; Ischemia; Knowledge; Label; Magnetic Resonance Imaging; Measures; Mediating; Membrane Potentials; Microscope; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Morphology; Mus; Neurologic; Neuronal Plasticity; Neurons; Oxygen; Oxygen Consumption; PECAM1 gene; Pathway interactions; Patients; Pattern; Permeability; Production; Rattus; Recombinants; Recovery; Recovery of Function; Recycling; Signal Pathway; Signal Transduction; Small Interfering RNA; Stem cells; Stroke; System; Testing; Time; Vascular remodeling; Western Blotting; angiogenesis; brain remodeling; cell injury; central nervous system injury; deprivation; extracellular; immunocytochemistry; improved; in vivo; kinase inhibitor; mitochondrial membrane; neural growth; neurovascular unit; neutralizing antibody; new therapeutic target; novel; optical imaging; particle; post stroke; progenitor; public health relevance; relating to nervous system; repaired; spatiotemporal; stroke recovery; synaptogenesis

 DESCRIPTION (provided by applicant): Reactive astrocytes were traditionally thought to induce both detrimental and beneficial effects for brain remodeling after stroke. Here, we propose a new concept whereby reactive astrocytes can surprisingly transfer mitochondria into adjacent neurons and endothelial cells to promote neurovascular remodeling in damaged brain. Our overall hypothesis is as follows. Damage associated molecular pattern (DAMP) signals upregulate CD38 in reactive astrocytes. In addition, accumulating endothelial progenitor cells (EPCs) secrete soluble CD31 that further amplify CD38 signaling. Altogether, this gliovascular crosstalk induces astrocytes to release of extracellular particles containing mitochondria. Mitochondria are then transferred into neurons and endothelium, thus enhancing neuroplasticity, BBB repair, angiogenesis and overall neurovascular recovery. Our pilot data are intriguing: (i) DAMPs or soluble CD31 upregulate CD38 in astrocytes, (ii) CD38 signaling causes astrocytes to release extracellular mitochondria, (iii) confocal microscopy reveals transfer of astrocytic mitochondria into neurons and endothelial cells, (iv) extracellular mitochondria enhance neural growth and angiogenesis, (v) suppression of astrocytic CD38 with siRNA inhibits neuronal plasticity after focal ischemia, and (vi) extracellular particles with functional mitochondria can e detected in CSF from human stroke patients. We will test 3 specific aims in this project. In Aim 1, we will investigate mechanisms of extracellular mitochondria particle production in reactive astrocytes. In Aim 2, we will dissect mechanisms of astrocytic mitochondria transfer for enhancing neurovascular remodeling. Finally in Aim 3, we will demonstrate that remodeling vascular signals promote mitochondria transfer from reactive astrocytes into neurons and endothelial cells after stroke in vivo. This study should define a novel mechanism of glial-EPCs crosstalk to enhance neurovascular remodeling and provide a new concept for mitochondrial transfer in the neurovascular unit.

 描述(申请人提供)：反应性星形胶质细胞传统上被认为对中风后的大脑重塑既有不利的影响，也有有益的影响。在这里，我们提出了一个新的概念，即反应性星形胶质细胞可以意外地将线粒体转移到邻近的神经元和内皮细胞中，以促进受损脑组织的神经血管重构。我们的总体假设如下。损伤相关分子模式(DAMP)信号上调反应性星形胶质细胞中的CD38。此外，积聚的内皮祖细胞(EPC)分泌可溶性CD31，进一步放大CD38信号。总之，这种胶质血管的串扰诱导星形胶质细胞释放含有线粒体的细胞外颗粒。线粒体随后被转移到神经元和内皮细胞，从而增强神经可塑性、血脑屏障修复、血管生成和整体神经血管恢复。我们的初步数据耐人寻味：(I)DAMPS或可溶性CD31上调星形胶质细胞中的CD38，(Ii)CD38信号导致星形胶质细胞释放细胞外线粒体，(Iii)共聚焦显微镜显示星形胶质细胞线粒体向神经元和内皮细胞转移，(Iv)细胞外线粒体促进神经生长和血管生成，(V)siRNA抑制星形细胞CD38表达抑制局部缺血后神经元的可塑性，(Vi)在人类中风患者的脑脊液中可检测到具有功能线粒体的细胞外颗粒。我们将在这个项目中测试3个具体目标。在目标1中，我们将研究反应性星形胶质细胞胞外线粒体颗粒产生的机制。在目标2中，我们将剖析星形细胞线粒体转移促进神经血管重塑的机制。最后，在目标3中，我们将在体内证明血管信号重塑促进线粒体从反应性星形胶质细胞向神经元和内皮细胞转移。这项研究将明确神经胶质-内皮祖细胞串扰促进神经血管重构的新机制，并为线粒体在神经血管单位的转移提供新的概念。