Restoring lost nigrostriatal fibers in Parkinson's disease based on clinically-inspired design criteria.
Restoring lost nigrostriatal fibers in Parkinson's disease based on clinically-inspired design criteria.
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DOI：
10.1016/j.brainresbull.2021.07.016
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发表时间：
2021-10
影响因子：
3.8
通讯作者：
Cullen DK
中科院分区：
文献类型：
--
作者：
Gordián-Vélez WJ;Chouhan D;España RA;Chen HI;Burdick JA;Duda JE;Cullen DK
帕金森氏症是一种神经退行性疾病，影响全球约1000万人。黑质中多巴胺能神经元和构成黑质纹状体通路的轴突纤维的死亡导致纹状体中多巴胺的损失，从而导致该疾病的运动症状。传统的治疗方法侧重于减轻症状，而使用人类胎儿或干细胞来源的神经元的治疗方法侧重于将这些细胞植入纹状体以恢复其神经支配。另一种方法是通路重建，其目的是以符合其解剖和生理的方式重建黑质纹状体通路的整个神经元和轴突纤维结构。这种类型的修复可能更有能力重建信号机制，以确保纹状体中适当的多巴胺释放和大脑中其他运动回路区域的调节。在这篇文章中，我们回顾了与通路重建作为帕金森病治疗相关的文献，深入研究了这些研究的局限性，并提出了在人类尺度上实现这一目标所需的设计标准。然后，我们展示了我们基于组织工程的平台，在体外制造水凝胶包裹的多巴胺能轴突束，用于随后植入大脑以取代和重建该通路。这些组织工程的黑质纹状体通路（TE-NSPs）可以通过细胞数量和表型、轴突生长长度和速率、突触连接能力和多巴胺释放来表征和优化。然后，我们展示了使用人类ipsc衍生的多巴胺能神经元和透明质酸水凝胶创建符合临床设计标准的这些结构的原始数据。最后，我们讨论了进一步优化人体规模te - nsp并将其转化为临床产品所需的未来步骤。
Parkinson’s disease is a neurodegenerative disease affecting around 10 million people worldwide. The death of dopaminergic neurons in the substantia nigra and the axonal fibers that constitute the nigrostriatal pathway leads to a loss of dopamine in the striatum that causes the motor symptoms of this disease. Traditional treatments have focused on reducing symptoms, while therapies with human fetal or stem cell-derived neurons have centered on implanting these cells in the striatum to restore its innervation. An alternative approach is pathway reconstruction, which aims to rebuild the entire structure of neurons and axonal fibers of the nigrostriatal pathway in a way that matches its anatomy and physiology. This type of repair could be more capable of reestablishing the signaling mechanisms that ensure proper dopamine release in the striatum and regulation of other motor circuit regions in the brain. In this manuscript, we conduct a review of the literature related to pathway reconstruction as a treatment for Parkinson’s disease, delve into the limitations of these studies, and propose the requisite design criteria to achieve this goal at a human scale. We then present our tissue engineering-based platform to fabricate hydrogel-encased dopaminergic axon tracts in vitro for later implantation into the brain to replace and reconstruct the pathway. These tissue-engineered nigrostriatal pathways (TE-NSPs) can be characterized and optimized for cell number and phenotype, axon growth lengths and rates, and the capacity for synaptic connectivity and dopamine release. We then show original data of advances in creating these constructs matching clinical design criteria using human iPSC-derived dopaminergic neurons and a hyaluronic acid hydrogel. We conclude with a discussion of future steps that are needed to further optimize human-scale TE-NSPs and translate them into clinical products.
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