在帕金森病大鼠模型中,负载胶质细胞系源性神经营养因子的冷冻凝胶微载体能增强原发性多巴胺能神经元的移植。

Kaushik Narasimhan, Abrar Hakami, Giulia Comini, Tommy Patton, Ben Newland, Eilís Dowd
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引用次数: 0

摘要

目的:由聚(乙二醇)二丙烯酸酯和丙烯酸 3-磺丙基酯制成的冷凝胶微载体有可能成为在大脑中长期保留神经营养因子的输送载体。此外,它们还能解决移植前体在大脑中因移植后神经营养被剥夺而导致的存活率不一和分化不良的局限性,从而有可能加强治疗帕金森病的干细胞衍生多巴胺能细胞替代策略。在此背景下,为了开发概念验证,本研究旨在通过评估GDNF负载的冷冻凝胶微载体对帕金森病大鼠脑内多巴胺能原始移植物的存活率和神经再支配的影响,确定其疗效:将胚胎第14天的大鼠腹侧中脑细胞移植到6-羟基多巴胺缺损的纹状体中,或单独移植,或与GDNF一起移植,或与无负载的冷冻凝胶微载体一起移植,或与负载GDNF的冷冻凝胶微载体一起移植。尸体解剖后,GDNF和酪氨酸羟化酶免疫染色分别用于鉴定植入的冷冻凝胶微载体中GDNF的保留情况,以及鉴定大脑中移植的多巴胺能神经细胞体和神经纤维:我们发现移植部位的GDNF染色冷冻凝胶微载体完好无损,这表明它们能够将输送的GDNF在大脑中长期保留4周。这使得移植的多巴胺能神经元存活率(1.9 倍)和纹状体再支配(密度和体积)均有所提高,此外,移植部位内的纤维萌发也有所增强:这一数据提供了一个重要的原理证明,即在帕金森病的细胞替代疗法中,神经营养素负载的冷冻凝胶微载体对细胞的移植具有有益影响。为实现临床转化,还需要进一步研究评估低温凝胶微载体对帕金森病大鼠脑内干细胞衍生多巴胺能前体的存活和分化的影响。
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Cryogel microcarriers loaded with glial cell line-derived neurotrophic factor enhance the engraftment of primary dopaminergic neurons in a rat model of Parkinson's disease.

Objective.Cryogel microcarriers made of poly(ethylene glycol) diacrylate and 3-sulfopropyl acrylate have the potential to act as delivery vehicles for long-term retention of neurotrophic factors (NTFs) in the brain. In addition, they can potentially enhance stem cell-derived dopaminergic (DAergic) cell replacement strategies for Parkinson's disease (PD), by addressing the limitations of variable survival and poor differentiation of the transplanted precursors due to neurotrophic deprivation post-transplantation in the brain. In this context, to develop a proof-of-concept, the aim of this study was to determine the efficacy of glial cell line-derived NTF (GDNF)-loaded cryogel microcarriers by assessing their impact on the survival of, and reinnervation by, primary DAergic grafts after intra-striatal delivery in Parkinsonian rat brains.Approach.Rat embryonic day 14 ventral midbrain cells were transplanted into the 6-hydroxydopamine-lesioned striatum either alone, or with GDNF, or with unloaded cryogel microcarriers, or with GDNF-loaded cryogel microcarriers.Post-mortem, GDNF and tyrosine hydroxylase immunostaining were used to identify retention of the delivered GDNF within the implanted cryogel microcarriers, and to identify the transplanted DAergic neuronal cell bodies and fibres in the brains, respectively.Main results.We found an intact presence of GDNF-stained cryogel microcarriers in graft sites, indicating their ability for long-term retention of the delivered GDNF up to 4 weeks in the brain. This resulted in an enhanced survival (1.9-fold) of, and striatal reinnervation (density & volume) by, the grafted DAergic neurons, in addition to an enhanced sprouting of fibres within graft sites.Significance.This data provides an important proof-of-principle for the beneficial effects of neurotrophin-loaded cryogel microcarriers on engraftment of cells in the context of cell replacement therapy in PD. For clinical translation, further studies will be needed to assess the impact of cryogel microcarriers on the survival and differentiation of stem cell-derived DAergic precursors in Parkinsonian rat brains.

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