Embryonic stem cell therapy after cervical contusion SCI in NHPs

项目摘要/摘要 这是我们的加州脊髓损伤(SCI)联盟提出的一项新的多PI提案，以继续翻译 从啮齿动物到灵长类动物的神经干细胞移植的令人兴奋的结果，并进行评估 非人灵长类(Nhp)颈挫伤脊髓损伤模型的有效性和安全性。我们的多中心 该联盟在一系列研究中检查了功能的恢复及其解剖学上的相关性 颈椎半横断模型。我们发现了皮质脊髓束的自发和广泛的可塑性 (CST)系统，这在以前的啮齿动物研究中没有得到重视。我们已经开发了第一个大型核电厂 颈椎偏缩性脊髓损伤模型、开放式评分系统和新型笼内前肢活动 并进行手部功能测试以评估功能结果。丰富的新信息和方向告诉我们 这种共享的方法对于使用非常有价值的灵长类模型的价值。这个项目的重点是翻译 我们的NHP干细胞起作用了。 我们现在报道，来自人脊髓的神经干细胞(NSCs)早期移植到半横断部位 NHP SCI，将大量轴突延伸到很长的距离，这些移植似乎 促进手功能的长期恢复，并支持CST再生进入移植物。神经干细胞源自 被批准的人类胚胎干细胞H9(H9 HESCNSCs)也支持CST向脊髓再生 脊髓损伤后NHP移植。此外，我们已经推进了我们的细胞治疗策略，以生产出第一批h9 hESCNSCs。 将它们拖向脊髓的命运，并表明将这些细胞移植到啮齿类动物身上 促进CST轴突更旺盛的再生。因此，在NHPS的这个提案中，我们将移植 在更慢性和临床相关的6周时间点，将hESCNSCs尾化为挫伤损伤。我们 假设这些移植物将支持健壮的CST再生并促进前肢功能的恢复， 并为CST轴突提供继电器，以影响C8-T1脊髓的前肢电路。我们将使用顺行 以及移植细胞的逆行示踪、免疫组化和转染，并将连接数据与恢复相关联， 并测试这些移植的长期存活率、安全性和功能效果。

PROJECT SUMMARY/ABSTRACT This is a new multi-PI proposal from our California Spinal Cord Injury (SCI) consortium to continue to translate exciting results from the transplantation of neural stem cells (NSCs) from rodent to primate, and to evaluate efficacy and safety in our non-human primate (NHP) cervical contusion SCI model. Our multi-center consortium has examined recovery of function and its anatomical correlates in a series of studies using a cervical hemisection model. We have discovered spontaneous and extensive plasticity of the corticospinal tract (CST) system that had not been appreciated in previous rodent studies. We have developed the first large NHP model of cervical hemicontusion SCI together with an open-field scoring system and novel in-cage forelimb activity and hand function tests to evaluate functional outcomes. The wealth of new information and directions speak to the value of this shared approach to using the very valuable primate model. This project focuses on translation of our NHP stem cell work. We now report that neural stem cells (NSCs) derived from human spinal cord grafted early to hemisection sites in NHP SCI, extend very large numbers of axons over very long distances, and that these transplants appear to enhance long-term recovery of hand function, and support CST regeneration into the graft. NSCs derived from the approved human embryonic stem cell H9 (H9 hESCNSCs) also support CST regeneration into spinal cord grafts in the NHP after SCI. Further, we have advanced our cell therapy strategy to produce the first H9 hESCNSCs caudalized to move them towards a spinal cord fate, and have shown that transplants of these cells in rodents promote much more vigorous regeneration of CST axons7. Therefore, in this proposal in NHPs, we will transplant caudalized hESCNSCs into a contusion lesion at a more chronic and clinically relevant six week time point. We hypothesize that these grafts will support robust CST regeneration and enhance recovery of forelimb function, and provide a relay for CST axons to influence forelimb circuitry in the C8-T1 cord. We will use anterograde and retrograde tracing, IHC and transfection of graft cells and correlate the connectional data with recovery, and test the long-term survival, safety, and functional effects of these transplants.