SCI Consortium Study: Neural Stem Cell Transplantation for Cervical Spinal Cord Injury

SCI 联盟研究：神经干细胞移植治疗颈脊髓损伤

• 批准号: 10699960
• 负责人: JOHN H. BROCK
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10699960
• 关键词: Acute; Adult; American; Anatomy; Animal Model; Animals; Axon; Brain; Cell Line; Cell Maturation; Cells; Cervical; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Contusions; Data; Development; Evaluation; Evolution; Extracellular Matrix; Goals; Healthcare Systems; Human; Human Cell Line; Human Development; Implant; Infection; Injury; Interneurons; Lead; Learning; Lesion; Longitudinal Studies; Maps; Modeling; Modification; Motor; Motor Neurons; Nature; Neuroglia; Neurons; Nude Rats; Outcome; Output; Phenotype; Rabies; Rabies virus; Rattus; Recovery; Research; Research Project Grants; Rodent; Safety; Sensory; Signal Transduction; Site; Spinal; Spinal Cord; Spinal Cord Contusions; Spinal Cord transection injury; Spinal cord injury; Stem cell transplant; Synapses; Techniques; Testing; Time; Translations; Transplantation; Variant; Vertebral column; Veterans; Work; axon guidance; cell type; cellular targeting; central gray matter; clinical translation; clinically relevant; collaborative environment; economic impact; efficacy evaluation; functional improvement; functional outcomes; human embryonic stem cell line; improved; injury and repair; innovation; lead candidate; nerve stem cell; nerve supply; neural; neural circuit; neurodevelopment; novel; novel strategies; novel therapeutics; programs; severe injury; stem cell biology; stem cell therapy; synaptogenesis; timeline; transmission process; white matter

Spinal cord injury (SCI) often damages, not only white matter axon tracts that transmits signals to and from the brain, but also the central gray matter, causing segmental loss of interneurons and motor neurons. Transplantation of neural stem cells (NSCs) has the potential to replace lost neurons and glia. These transplanted neurons can form functional relays between spinal segments disconnected by the injury. We have generated human NSCs with a spinal cord identity to test the hypothesis that spinal cord NSCs will more appropriately integrate into sites of the injured spinal cord. Our preliminary data provide evidence that both rat and human neural stem cells can be transplanted into multiple models of SCI, including a clinically relevant contusion model. However, humans NSCs appear to develop on a longer timeline, more similar to human development. Therefore, we aim to characterize the maturation and phenotype of human spinal cord NSCs (scNSCs). Long-term studies will assess the efficacy, safety and synaptic integration of such scNSC therapy in a clinically relevant contusive model of cervical SCI. This work is highly innovative and clinically oriented: 1) We will utilize a contusion type injury that is most applicable to human SCI. 2) We will examine a novel human NSC line with a spinal cord identity (scNSCs). 3) Long-term studies will examine the maturation, efficacy and safety of scNSCs, our lead cell candidate, for the treatment of spinal cord injury. 4) Novel trans-synaptic tracing techniques will be used to assess the synaptic integration of both host inputs to the graft and graft outputs to host motor neurons.

脊髓损伤 (SCI) 不仅会损害向神经传递信号的白质轴突束， 来自大脑，也来自中央灰质，导致中间神经元和运动神经元的节段性损失 神经元。神经干细胞（NSC）移植有可能替代丢失的神经元 神经胶质细胞。这些移植的神经元可以在断开的脊柱节段之间形成功能中继 因受伤。我们已经生成了具有脊髓特性的人类 NSC，以检验以下假设： 脊髓 NSC 将更合适地整合到受损脊髓部位。我们的 初步数据证明大鼠和人类神经干细胞都可以移植到 SCI 的多种模型，包括临床相关的挫伤模型。然而，人类 NSC 似乎发展的时间更长，更类似于人类的发展。因此，我们的目标是 表征人类脊髓 NSC (scNSC) 的成熟和表型。长期学习 将评估此类 scNSC 疗法在临床中的功效、安全性和突触整合 颈椎SCI相关挫伤模型。 这项工作具有高度创新性和临床导向： 1) 我们将采用最适用于人类 SCI 的挫伤型损伤。 2) 我们将研究一种具有脊髓特性的新型人类 NSC 系 (scNSC)。 3) 长期研究将检验我们的主导细胞 scNSC 的成熟度、功效和安全性 候选人，用于治疗脊髓损伤。 4）新型跨突触追踪技术将用于评估两个宿主的突触整合 移植物的输入和宿主运动神经元的移植物输出。