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

创伤性脑损伤是世界范围内导致死亡和残疾的主要原因，是一个高度相关的医学和社会经济问题。多能干细胞衍生品移植在脑外伤的治疗中具有巨大的潜力。我们推测，诱导多能干细胞源性神经前体细胞(iPS-NPC)移植可以改善脑外伤后的功能结局，全身联合应用神经源性和神经保护性化合物可以提高脑损伤动物的存活率、植入率、治疗效果和安全性。在侧向液压冲击局灶性脑损伤后，免疫抑制的大鼠将接受一次立体定向注射表达人EGFP和荧光素酶的IPSC-NP，并在体外毒性试验中发现该化合物对IPSC-NP具有最好的保护作用。利用脑外伤后最有效的细胞剂量和最佳移植时间点，将通过一系列神经行为测试来评估移植的神经前体细胞的功能益处。细胞存活将通过体内生物发光成像进行监测，免疫组织学分析将用于确定内源性细胞移植的位置、植入、迁移、短期安全性和连接性。这些分析将增加我们对人IPSC-NPC与神经保护化合物联合使用的治疗潜力的了解，并为未来的后续研究提供基础，在这些研究中，可以进一步探索这一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。

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.