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

• 批准号: 8280318
• 负责人: LING WEI
• 金额: $ 19.38万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280318
• 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; 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; tissue repair; vector

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.

描述（由申请人提供）：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有前途的有效疗法。移植的细胞通过不同的机制显示出治疗益处，包括增强营养支持以及补充丢失的细胞和大脑结构。在被认为是基于细胞的治疗的有用候选细胞的几种细胞类型中，胚胎干（ES）细胞因其在体外和移植到缺血区后发育成神经元和非神经元细胞的能力而受到了极大的关注。脑。阻碍细胞疗法效率和功效的两个主要障碍是移植细胞的存活率和轴突生长不足。此外，也许更重要的是，如何引导移植的细胞形成正确的神经网络并产生功能恢复仍然悬而未决。这个问题与临床极为相关，但迄今为止它在很大程度上被忽视了。利用大鼠独特的须管皮层中风模型，本研究采用了新的策略，将显着增强移植细胞的耐受性，并显着促进移植神经祖细胞的目标特异性轴突生长，促进宿主神经网络/通路内的有组织整合缺血的大脑。具体目标 1 将在干细胞治疗中应用低氧预处理 (HP) 的充分表征的保护机制。小鼠胚胎干细胞衍生的神经祖细胞 (ESNPC) 将经过 HP 预处理，然后进行测试以提高中风后大脑的存活率。具体目标 2 将测试表达神经元特异性和分泌型 RhoA 抑制剂 C3 转移酶的移植 ESNPC 的轴突生长增强情况。我们将测试 C3 的局部表达/递送促进目标特异性（桶状皮层）轴突生长的假设。胡须刺激产生的传入输入信号将进一步加强定向再生。将评估皮质内和丘脑皮质连接的形态修复。具体目标 3 将致力于针对胡须-丘脑-桶状皮层通路的功能评估。再生桶状皮质中的光学成像、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-ESNPCs 实现功能恢复提供令人信服的证据。这项研究将基础研究和转化研究中的一些令人兴奋的进展应用到一种有前景的缺血性中风联合疗法中。我们的长期目标是开发有效、安全、可行的策略，将干细胞疗法推进临床应用。