Prolonged human neural stem cell maturation supports recovery in injured rodent CNS
Prolonged human neural stem cell maturation supports recovery in injured rodent CNS
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DOI：
10.1172/jci92955
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发表时间：
2017-09-01
影响因子：
15.9
通讯作者：
Tuszynski, Mark H.
中科院分区：
文献类型：
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作者：
Lu, Paul;Ceto, Steven;Tuszynski, Mark H.
神经干细胞(NSCs)可以分化为神经元和神经胶质细胞，使用人类NSCs的策略有可能恢复脊髓损伤(SCI)后的功能。然而，人神经干细胞在成年损伤的中枢神经系统中成熟的时间并没有明确的定义，这给基于神经干细胞的治疗的设计和实施提出了根本的问题。这项工作评估了在1.5年内植入免疫缺陷大鼠脊髓损伤部位的人H9神经干细胞。值得注意的是，移植物在整个评估期内显示出继续成熟的证据。神经元成熟度的标志在移植后3个月首次表达。然而，在接下来的一年中，神经发生、神经元修剪和神经元扩大仍在继续，而总的移植物大小随着时间的推移保持稳定。大量轴突很早就从移植物中长出，其中一半的投射持续了1.5年。成熟的星形胶质细胞标记物最早出现在移植后6个月，而更成熟的少突胶质细胞标记物直到移植后1年才出现。星形胶质细胞慢慢从移植物中迁移出来。值得注意的是，移植后1年多开始功能恢复。因此，尽管移植到受损的啮齿动物脊髓中，人类神经干细胞仍保持着人类固有的成熟率，但它们支持延迟的功能恢复，这一发现对计划人类临床试验非常重要。
Neural stem cells (NSCs) differentiate into both neurons and glia, and strategies using human NSCs have the potential to restore function following spinal cord injury (SCI). However, the time period of maturation for human NSCs in adult injured CNS is not well defined, posing fundamental questions about the design and implementation of NSC-based therapies. This work assessed human H9 NSCs that were implanted into sites of SCI in immunodeficient rats over a period of 1.5 years. Notably, grafts showed evidence of continued maturation over the entire assessment period. Markers of neuronal maturity were first expressed 3 months after grafting. However, neurogenesis, neuronal pruning, and neuronal enlargement continued over the next year, while total graft size remained stable over time. Axons emerged early from grafts in very high numbers, and half of these projections persisted by 1.5 years. Mature astrocyte markers first appeared after 6 months, while more mature oligodendrocyte markers were not present until 1 year after grafting. Astrocytes slowly migrated from grafts. Notably, functional recovery began more than 1 year after grafting. Thus, human NSCs retain an intrinsic human rate of maturation, despite implantation into the injured rodent spinal cord, yet they support delayed functional recovery, a finding of great importance in planning human clinical trials.