Stem cell transplantation therapy via intranasal delivery after stroke

 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有前途的再生疗法。在基于细胞的治疗的几种细胞类型中，诱导多能干细胞(IPS)由于其能够发展为神经元和非神经元细胞、自体移植的可能性以及缺乏伦理争议而受到极大的关注。不幸的是，这些由基因组整合的病毒载体创造的细胞有潜在的肿瘤生长风险。此外，目前的细胞输送方法要么是侵入性的，要么是低效的；移植的细胞会受到 宿主脑缺血区细胞存活率低，对病变部位归巢不足。基于我们在使用干细胞和神经前体细胞治疗中风方面的最新进展和鼻腔内药物/营养因子输送的经验，我们现在建议测试经低氧预适应(HP)处理的脱毒人iPS-神经前体经鼻内输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卒中后的治疗效果。具体目的1检测幽门螺杆菌策略和CXCR-4在体外对人iPS-NP细胞定向迁移的促进作用。Hp处理、CXCR-4和/或FAK表达细胞的基因调控和分化将被检测。特定目标2将在我们独特的小鼠桶状皮质卒中模型中测试目标1中的策略的治疗效果，期望在鼻腔给药后改善存活率、分化和增强iPS-NP归巢到缺血皮质。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，以恢复局灶性脑缺血损伤后皮质和丘脑皮质的连接和感觉运动活动。这项研究利用了我们合作团队中互补的专业知识，并基于最近在干细胞研究和中风治疗方面开发的新策略。我们的最终目标是开发一种非侵入性的、高效的、更有效的基于细胞的治疗方法，用于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.