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Gene therapy and cellular transplantation; Towards a combination strategy for spinal cord injury repair.

机译：基因治疗和细胞移植；寻求脊髓损伤修复的联合策略。

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摘要

The combination of viral mediated gene delivery, tissue engineering, and Schwann cell (SC) transplantation offer a promising strategy to enhance axonal regeneration and functional recovery following spinal cord injury (SCI). The rationale and feasibility of using such combination has been extensively reviewed in Chapter 1.; The study presented in Chapter 2 showed that lentiviral vectors are most suitable in situations where stable long term transgene expression is needed, while adenovirus and retrovirus are more suited for transient gene delivery.; Tissue engineering combined with Schwann cell (SC) transplantation is a promising method to enhance regeneration and remyelination of axons following a thoracic spinal cord injury (SCI). Previously, SCs in semi-permeable guidance channels made of polyacrylonitrile and polyvinylchloride (PAN/PVC) copolymers were shown to promote the growth of axons into the graft environment. In Chapter 3, we test whether different PAN/PVC mini-channel geometries affects axonal regeneration, we compared three types of channels, i.e. channels with smooth inner wall, channels with grooved inner wall, and channels filled with filaments using this model. Our results showed that grooving of the channel inner wall along the axis of the channel resulted in a significantly higher number (730.66+/-252.76) of myelinated axons at the channel mid-point, compared to the channels with smooth inner wall (539.4+/-287.63; p0.01), indicating an enhancement of axonal regeneration when grooves are provided within the channel. In contrast, channels filled with filaments had a significantly lower number of myelinated axons (163.54+/-76.04) than both the grooved and smooth inner wall channels (p0.001), indicating that densely-packed filaments prohibited axonal growth into the channel. This type of channels may need to be modified to incorporate growth-promoting molecules on filament surface and/or decrease the number of filaments inside the channel to provide attractiveness and/or space for more axons to grow. We conclude that the use of channels with grooved inner wall, combination with seeded SCs, is more suitable for axonal regeneration and myelination following SCI than the other two channel types. This combination can be used in further studies with the addition of regeneration enhancing factors such as neurotrophins.; In Chapter 4, we examined axonal regeneration following transplantation of PAN/PVC mini-channel seeded with SCs that were infected with 3 viral vectors, i.e. retroviral, adenoviral, and lentiviral vectors. Although, animals in LZRS-DI5A SCs group had a significantly lower number of myelinated axons compared to lentiD15A group they showed significant improvement in grid walking test. We conclude that different patterns of transgene expression may enhance regeneration and myelination of different populations of regenerating axons following thoracic SCI.; In conclusion, combination strategies for SCI using different transgene expression patterns and different channel inner wall geometry enhance axonal regeneration and myelination. Functional recovery however, may be the result of reorganization of spinal cord circuitry rather than successful axonal regeneration.
机译：病毒介导的基因传递，组织工程和施万细胞（SC）移植的结合提供了一种有希望的策略，可增强脊髓损伤（SCI）后轴突再生和功能恢复。第1章对使用这种组合的理由和可行性进行了广泛的审查。第二章的研究表明，慢病毒载体最适合需要稳定的长期转基因表达的情况，而腺病毒和逆转录病毒更适合瞬时基因的传递。组织工程与雪旺细胞（SC）移植相结合是一种有希望的方法，可增强胸脊髓损伤（SCI）后轴突的再生和髓鞘再生。以前，由聚丙烯腈和聚氯乙烯（PAN / PVC）共聚物制成的半透性引导通道中的SC可以促进轴突生长到接枝环境中。在第3章中，我们测试了不同的PAN / PVC微型通道几何形状是否会影响轴突再生，我们使用此模型比较了三种类型的通道，即内壁光滑的通道，内壁带凹槽的通道和填充细丝的通道。我们的结果表明，与光滑内壁的通道（539.4+）相比，沿着通道轴的通道内壁的开槽导致通道中点的髓鞘轴突的数量显着增加（730.66 +/- 252.76） /-287.63；p<0.01），表明当在通道内提供凹槽时轴突再生增强。相比之下，充满细丝的通道的髓鞘轴突数量（163.54 +/- 76.04）明显少于带凹槽的光滑内壁通道（p <0.001），这表明密堆积的细丝会阻止轴突生长到通道中。可能需要修改这种类型的通道，以在长丝表面上掺入促进生长的分子和/或减少通道内的长丝数量，从而为更多的轴突提供吸引力和/或空间。我们得出的结论是，与其他两种通道类型相比，使用带有沟槽内壁的通道和种子SC的组合更适合SCI后的轴突再生和髓鞘形成。该组合可与其他再生增强因子（例如神经营养蛋白）一起用于进一步的研究。在第4章中，我们检查了用SC感染的PAN / PVC微型通道移植的轴突再生，SC感染了3种病毒载体，即逆转录病毒，腺病毒和慢病毒载体。尽管与lentiD15A组相比，LZRS-DI5A SCs组中的动物的髓鞘轴突数量明显减少，但它们在走网试验中显示出显着的改善。我们得出的结论是，不同的转基因表达方式可以增强胸廓脊髓脊髓损伤后不同轴突再生群体的再生和髓鞘形成。总之，使用不同转基因表达方式和不同通道内壁几何结构的SCI组合策略可增强轴突再生和髓鞘形成。然而，功能恢复可能是脊髓电路重组而不是成功的轴突再生的结果。

著录项

  • 作者

    Abdellatif, Ahmed Abdelzaher.;

  • 作者单位

    University of Louisville.;

  • 授予单位 University of Louisville.;
  • 学科 Biology Neuroscience.; Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 127 p.
  • 总页数 127
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;
  • 关键词

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