Stem cell transplantation therapy via intranasal delivery after stroke

 描述（由申请人提供）：干细胞移植为脑缺血和其他CNS疾病提供了一种有前途的再生疗法。在用于基于细胞的治疗的几种细胞类型中，诱导多能干细胞（iPS）由于其发育成神经元和非神经元细胞的能力、自体移植的可能性和缺乏伦理争议而受到极大关注。不幸的是，这些由基因组整合的病毒载体产生的细胞具有肿瘤生长的潜在风险。此外，目前的细胞递送方法要么是侵入性的，要么是低效的;移植的细胞遭受感染。 宿主缺血性脑中细胞存活率差和不能充分归巢到损伤部位。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，用于增强局灶性缺血性中风后的治疗益处。具体目标1将检查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将测试目标1中的策略在我们独特的小鼠桶状皮质层模型中的治疗效果，期望在鼻内递送后iPS-NPC改善存活、分化和增强归巢至缺血皮质。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，以恢复皮质内和丘脑皮质连接以及局灶性缺血损伤后的感觉运动活动。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的，但高效和更有效的细胞为基础的治疗缺血性中风的临床治疗。

 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.