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Promoting axonal growth and tissue repair in stem cell therapy after stroke

中风后干细胞治疗促进轴突生长和组织修复

基本信息

批准号：
8163153
负责人：
LING WEI
金额：
$ 23.25万
依托单位：
EMORY UNIVERSITY
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：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8163153
关键词：
Address Adult Affect Animals Attention Axon Bacterial exotoxin Basic Science Behavioral Biological Neural Networks Brain Brain Injuries Brain Ischemia Cell Proliferation Cell Therapy Cell Transplants Cells Central Nervous System Diseases Cerebral Ischemia Clinical Clinical Trials Combined Modality Therapy Cues Cultured Cells Development Environment Failure Family Forelimb Generations Goals Growth Guanosine Triphosphate Phosphohydrolases Human Hypoxia Implant In Vitro Injury Investigation Ischemia Ischemic Stroke Lentivirus Vector Limb structure Mediating Modeling Molecular Monomeric GTP-Binding Proteins Motor Mus Natural regeneration Neurites Neuroglia Neurons Organ Outcome Pathway Analysis Pathway interactions Performance Peripheral Peripheral Nerves Play Process Property Pyramidal Cells Rattus Recovery of Function Replacement Therapy Research Infrastructure Role Signal Transduction Site Specificity Stem cell transplant Stimulus Stroke Structure Synapses Testing Thalamic structure Therapeutic Thick Time Training Transferase Translational Research Transplantation Vibrissae Viral Vector Work Wound Healing angiogenesis axon growth axon regeneration barrel cortex base brain cell brain repair cell motility cell type central nervous system injury clinical application clinically relevant constraint induced therapy density design embryonic stem cell glucose metabolism improved in vivo inhibitor/antagonist ischemic lesion juvenile animal mature animal nerve stem cell neurite growth neurogenesis novel novel strategies optical imaging post stroke preconditioning prevent regenerative repaired rho stem cell therapy vector

项目摘要

DESCRIPTION (provided by applicant): Stem cell transplantation offers a promising efficacious therapy for cerebral ischemia and other CNS disorders. Transplanted cells show therapeutic benefits via different mechanisms, including enhanced trophic support and the replenishment of lost cells and brain structures. Of the several cell- types considered useful candidates for cell-based therapeutics, embryonic stem (ES) cells have received a great deal of attention due to their ability to develop into neurons and non-neuronal cells both in vitro and after transplantation into the ischemic brain. Two major hurdles that have hindered the efficiency and efficacy of cell-based therapy are the insufficient survival and axonal outgrowth of transplanted cells. Moreover, and perhaps more importantly, how the transplanted cells can be directed to form correct neural networks and produce functional recovery is still unresolved. This issue is extremely clinically relevant, yet so far it has been largely ignored. Using the unique whisker-barrel cortex stroke model in rats, the present investigation incorporates novel strategies that will markedly enhance the tolerance of transplanted cells and significantly facilitate target-specific axonal growth of transplanted neural progenitors, promoting organized integration within host neural network/pathways in the ischemic brain. Specific Aim 1 will apply the well-characterized protective mechanism of hypoxic preconditioning (HP) in stem cell therapy. Mouse embryonic stem cell-derived neural progenitor cells (ESNPCs) will be HP pretreated and then tested for enhanced survival in the post-stroke brain. Specific Aim 2 will test the enhancement of axonal growth of transplanted ESNPCs that express the neuron-specific and secretable RhoA inhibitor C3 transferase. We will test the hypothesis that localized expression/delivery of C3 promotes target-specific (barrel cortex) axonal outgrowth. The directed regeneration will be further strengthened by afferent input signals generated by whisker stimulation. The morphological repair of intracortical and thalamocortical connections will be evaluated. Specific Aim 3 will be devoted to the functional assessments specific for the whisker-thalamus-barrel cortex pathway. Optical imaging, electrophysiological recordings and local glucose metabolism in the regenerated barrel cortex will provide compelling evidence for the functional recovery achieved by transplantation of HP-ESNPCs in the enriched environment. This investigation will apply some exciting progress in basic and translational research into a promising combination therapy for ischemic stroke. Our long term goal is to develop effective, safe, and feasible strategies to advance stem cell therapy into clinical applications. PUBLIC HEALTH RELEVANCE: Transplantation therapy using mouse ES cell-derived neural progenitor cells will be tested in a rat ischemia model targeting the whisker-barrel cortex. We will address three key issues in transplantation: 1) to promote survival of ESC-derived neural cells after transplantation; 2) to promote directed axonal growth of transplanted neural progenitors; 3) to guide and improve the repair process and functional recovery in the whisker-thalamocortical-barrel cortext pathway after the transplantation therapy.

描述(申请人提供)：干细胞移植为脑缺血和其他中枢神经系统疾病提供了一种很有前途的有效治疗方法。移植的细胞通过不同的机制显示出治疗的好处，包括增强营养支持和补充丢失的细胞和大脑结构。在被认为是基于细胞治疗的几种细胞类型中，胚胎干细胞(ES)由于其在体外和移植到缺血脑中后能够发育为神经元和非神经元细胞的能力而受到极大的关注。阻碍细胞治疗效率和疗效的两个主要障碍是移植细胞的存活不足和轴突生长。此外，也许更重要的是，移植细胞如何被引导形成正确的神经网络并产生功能恢复仍未解决。这个问题在临床上非常相关，但到目前为止，它在很大程度上被忽视了。利用独特的大鼠胡须桶状皮质卒中模型，本研究采用了新的策略，显著提高了移植细胞的耐受性，显著促进了移植神经前体细胞靶向性轴突的生长，促进了缺血脑内宿主神经网络/通路的有组织整合。具体目标1将在干细胞治疗中应用低氧预适应(HP)已有的保护机制。小鼠胚胎干细胞来源的神经前体细胞(ESNPC)将经过HP预处理，然后测试其在中风后大脑中的存活情况。特定目标2将测试表达神经元特异性和分泌性RhoA抑制物C3转移酶的移植的ESNPC对轴突生长的促进作用。我们将检验这一假设，即C3的局部表达/传递促进靶点特异性(桶状皮质)轴突的生长。胡须刺激产生的传入输入信号将进一步加强定向再生。将对皮质内和丘脑皮质连接的形态修复进行评估。具体目标3将专门用于针对胡须-丘脑-桶状皮质通路的功能评估。再生桶状皮质的光学成像、电生理记录和局部葡萄糖代谢将为在丰富的环境中移植HP-ESNPC实现功能恢复提供强有力的证据。这项研究将在基础和转化性研究中应用一些令人兴奋的进展，以期成为一种有前景的缺血性中风的联合疗法。我们的长期目标是开发有效、安全和可行的策略，推动干细胞治疗进入临床应用。公共卫生相关性：使用小鼠胚胎干细胞来源的神经前体细胞的移植疗法将在以胡须桶皮质为靶点的大鼠缺血模型中进行测试。我们将解决移植中的三个关键问题：1)促进干细胞来源的神经细胞移植后的存活；2)促进移植神经前体细胞的定向轴突生长；3)指导和改善移植治疗后胡须-丘脑皮质桶通路的修复过程和功能恢复。