Stem cell transplantation therapy via intranasal delivery after stroke

中风后鼻内输送干细胞移植治疗

• 批准号: 9104350
• 负责人: LING WEI
• 金额: $ 34.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104350
• 关键词: Address; Adult; Animal Model; Animals; Attention; Autologous; Autologous Transplantation; Biological Neural Networks; Blood - brain barrier anatomy; Brain; Bypass; CXCR4 Receptors; CXCR4 gene; Cell Culture Techniques; Cell Survival; Cell Therapy; Cell Transplantation; Cell Transplants; Cells; Central Nervous System Diseases; Cerebral Ischemia; Chemotactic Factors; Clinical; Clinical Treatment; Clinical Trials; Electrophysiology (science); Environment; Ethics; Face; Gene Expression Regulation; Gene-Modified; Generations; Genomics; Goals; Health; Home environment; Homing; Human; Hypoxia; In Vitro; Intranasal Administration; Investigation; Ischemia; Ischemic Stroke; Lead; Lesion; Life; Mediating; Methods; Modeling; Molecular; Mus; Natural regeneration; Neuroglia; Neuronal Differentiation; Neurons; PTK2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Recovery of Function; Research; Rest; Risk; Route; Signal Transduction; Site; Somatic Cell; Stem Cell Research; Stem cell transplant; Stem cells; Stroke; Stromal Cell-Derived Factor 1; Techniques; Testing; Therapeutic; Therapeutic Effect; Transplantation; Viral Vector; Virus; barrel cortex; base; behavior test; brain tissue; cell motility; cell type; clinical application; effective therapy; expectation; experience; improved; in vivo; induced pluripotent stem cell; migration; mouse model; nerve stem cell; novel; novel strategies; optical imaging; post stroke; preconditioning; public health relevance; regenerative; regenerative therapy; repaired; research study; restoration; stem; stem cell therapy; stroke therapy; stroke treatment; synaptogenesis; tissue repair; tumor; tumor growth; vector

 DESCRIPTION (provided by applicant): Stem cell transplantation offers a promising regenerative therapy for cerebral ischemia and other CNS disorders. Of the several cell types for cell-based therapeutics, induced pluripotent stem (iPS) cells have received a great deal of attention due to their ability to develop into neurons and non-neuronal cells, the possibility of autologous transplantation and the lack of ethical controversies. These cells created by viral vectors of genomic integration, unfortunately, have a potential risk of tumor growth. In addition, current methods of cell delivery are either invasive or inefficient; transplanted cells suffer from poor cell survival in the host ischemic brain and insufficient homing to the lesion site. Based on our recent progress in stroke therapy using stem cells and neural progenitor cells (NPCs) and the experience in intranasal drug/trophic factor delivery, we now propose to test intranasal delivery of virus-free human iPS-NPCs pretreated with hypoxic preconditioning (HP) as a non-invasive and brain specific transplantation method for enhanced therapeutic benefits after focal ischemic stroke. Specific Aim 1 will examine the promoting effect of HP strategy and CXCR-4 expression in human iPS-NPCs on directed cell migration in vitro. Gene regulation and differentiation of HP-treated, CXCR-4 and/or FAK expressing cells will be examined. Specific Aim 2 will test the therapeutic effects of the strategies in Aim 1 in our unique barrel cortex stroe model of mice, with the expectation of improved survival, differentiation, and enhanced homing of iPS- NPCs to the ischemic cortex after intranasal delivery. Specific Aim 3 will examine neural network repair and functional recovery after the iPS-NPC therapy for restoration of the intracortical and thalamocortical connections and sensorimotor activity after the focal ischemic damage. This investigation takes advantage of the complementary expertise in our collaborative team and is based on recently developed novel strategies in stem cell research and stroke therapy. Our ultimate goal is to develop a non-invasive yet highly effective and more efficient cell-based therapy for clinical treatment of ischemic stroke.

 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再生疗法。在用于细胞治疗的几种细胞类型中，诱导多能干细胞（iPS）因其发育成神经元和非神经元细胞的能力、自体移植的可能性以及缺乏伦理争议而受到了极大的关注。不幸的是，这些由基因组整合病毒载体产生的细胞具有潜在的肿瘤生长风险。此外，目前的细胞递送方法要么是侵入性的，要么是效率低下的。移植的细胞患有 宿主缺血脑中的细胞存活率低，并且无法充分归巢至病变部位。基于我们在使用干细胞和神经祖细胞（NPC）治疗中风方面的最新进展以及鼻内药物/营养因子递送的经验，我们现在建议测试经低氧预处理（HP）预处理的无病毒人iPS-NPC的鼻内递送作为一种非侵入性和脑特异性移植方法，以增强局灶性缺血性中风后的治疗效果。具体目标1将考察HP策略和人iPS-NPC中CXCR-4表达对体外定向细胞迁移的促进作用。将检查 HP 处理的 CXCR-4 和/或 FAK 表达细胞的基因调控和分化。具体目标 2 将在我们独特的小鼠桶状皮质模型中测试目标 1 中策略的治疗效果，期望提高 iPS-NPC 的存活率、分化率，并增强鼻内递送后 iPS-NPC 向缺血皮质的归巢。具体目标 3 将检查 iPS-NPC 治疗后的神经网络修复和功能恢复，以恢复局灶性缺血损伤后皮质内和丘脑皮质连接以及感觉运动活动。这项研究利用了我们合作团队的互补专业知识，并基于最近开发的干细胞研究和中风治疗的新策略。我们的最终目标是开发一种非侵入性但高效且更高效的细胞疗法来临床治疗缺血性中风。