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有希望的有效疗法。移植的细胞通过不同的机制显示出治疗益处，包括增强的营养支持以及损失的细胞和脑结构的补充。在几种被认为是基于细胞疗法的有用候选物的细胞类型中，胚胎干细胞（ES）细胞因其在体外和移植到缺血性脑后发展成神经元和非神经元细胞的能力而受到了很大的关注。妨碍基于细胞治疗的效率和功效的两个主要障碍是移植细胞的存活率和轴突产物不足。此外，也许更重要的是，如何将移植的细胞定向以形成正确的神经网络并产生功能恢复。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略了。使用大鼠中独特的晶须桶皮层中风模型，本研究结合了新型策略，这些策略将显着增强移植细胞的耐受性，并显着促进了移植神经祖细胞的靶向特异性轴突生长，从而促进缺血性脑中宿主神经网络中有组织的整合。具体目标1将在干细胞疗法中应用良好的低氧预处理（HP）保护性机制。小鼠胚胎干细胞衍生的神经祖细胞（ESNPC）将进行HP预处理，然后测试中风后脑的生存增强。具体目标2将测试表达神经元特异性且可分泌的RhoA抑制剂C3转移酶的移植ESNPC的轴突生长的增强。我们将检验以下假设：C3的局部表达/递送促进靶标特异性（桶形皮层）轴突生长。通过晶须刺激产生的传入输入信号将进一步增强定向的再生。将评估心脏内和丘脑皮质连接的形态修复。具体目标3将专门用于针对晶须 - 甲状腺桶皮层途径的功能评估。再生桶皮层中的光学成像，电生理记录和局部葡萄糖代谢将为通过在富集环境中移植HP-ESNPC实现的功能恢复提供令人信服的证据。这项调查将在基础研究和转化研究中应用一些令人兴奋的进展，用于缺血性中风的有前途的组合疗法。我们的长期目标是制定有效，安全和可行的策略，以将干细胞疗法推向临床应用。