Regenerative potential of combined administration of iPS cell-derived neural progenitor cells and neuroprotective compounds in a rat model of focal traumatic brain injury

iPS 细胞衍生的神经祖细胞和神经保护化合物联合给药在局灶性脑外伤大鼠模型中的再生潜力

• 批准号: 261920491
• 负责人: Professor Dr. Edmund A. M. Neugebauer
• 金额: --
• 依托单位: Institut für Neurophysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/261920491?language=en
• 关键词: Regenerative; potential; combined; administration; iPS

Traumatic brain injury (TBI) is the leading cause of death and disability worldwide, thus representing a highly relevant medical and socio-economic problem. Transplantation of pluripotent stem cell derivatives holds great potential for the treatment of TBI. We hypothesize that transplantation of induced pluripotent stem cell-derived neural progenitor cells (iPS-NPCs) may improve the functional outcome after TBI and that the systemic co-administration of proneurogenic and neuroprotective compounds to animals with TBI can enhance their survival, engraftment, therapeutic efficacy and safety. After lateral fluid percussion focal brain injury the immunosuppressed rats will receive one stereotactic injection of human eGFP- and luciferase-expressing iPSC-NPCs with or without the compound found to have the best protective activity on iPSC-NPCs in toxicity assays in vitro. Utilizing the most effective cell dose and the best time point of transplantation after TBI the functional benefit of transplanted NPCs will be assessed using an array of neurobehavioral tests. The cell survival will be monitored by in vivo bioluminescence imaging and immunohistological analyses will be employed to determine the location, engraftment, migration, short-term safety and connectivity of transplanted with endogenous cells. These analyses will increase our understanding of the therapeutic potential of human iPSC-NPCs in combination with neuroprotective compounds and provide a basis for future follow-up studies in which the long-term safety and efficacy of this new therapeutic concept, exact mechanism of its therapeutic action, types of interactions of transplanted cells with the recipient cells can be further explored with the ultimate aim to translate iPSC-based concepts into human therapy.

创伤性脑损伤（TBI）是全世界死亡和残疾的主要原因，因此是一个高度相关的医疗和社会经济问题。多能干细胞衍生物移植治疗创伤性脑损伤具有很大的潜力。我们推测，诱导多能干细胞衍生的神经祖细胞（iPS-NPCs）移植可能改善TBI后的功能结局，而对TBI动物系统地联合给予前神经源性和神经保护化合物可以提高它们的存活、移植、治疗效果和安全性。在局部脑损伤后，免疫抑制大鼠接受一次立体定向注射表达人eGFP和荧光素酶的ipsc - npc，并在体外毒性试验中发现对ipsc - npc具有最佳保护活性的化合物。利用最有效的细胞剂量和TBI后移植的最佳时间点，移植的npc的功能益处将通过一系列神经行为测试进行评估。通过体内生物发光成像监测细胞存活，并通过免疫组织学分析确定移植细胞与内源性细胞的位置、植入、迁移、短期安全性和连通性。这些分析将增加我们对人类ipsc - npc联合神经保护化合物的治疗潜力的理解，并为未来的后续研究提供基础，进一步探索这种新的治疗概念的长期安全性和有效性，其治疗作用的确切机制，移植细胞与受体细胞的相互作用类型，最终目的是将基于ipsc的概念转化为人类治疗。