BACKGROUND & AIMS:
:Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease (PD), in which neurons of the substantia nigra (SN) die and fail to provide the neurotransmitter, dopamine (DA), to the striatum. We report that undifferentiated human neural stem cells (hNSCs) implanted into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian primates survived, migrated, and had a functional impact as assessed quantitatively by behavioral improvement in this DA-deficit model, in which Parkinsonian signs directly correlate to reduced DA levels. A small number of hNSC progeny differentiated into tyrosine hydroxylase (TH) and/or dopamine transporter (DAT) immunopositive cells, suggesting that the microenvironment within and around the lesioned adult host SN still permits development of a DA phenotype by responsive progenitor cells. A much larger number of hNSC-derived cells that did not express neuronal or DA markers was found arrayed along the persisting nigrostriatal path, juxtaposed with host cells. These hNSCs, which express DA-protective factors, were therefore well positioned to influence host TH+ cells and mediate other homeostatic adjustments, as reflected in a return to baseline endogenous neuronal number-to-size ratios, preservation of extant host nigrostriatal circuitry, and a normalizing effect on alpha-synuclein aggregation. We propose that multiple modes of reciprocal interaction between exogenous hNSCs and the pathological host milieu underlie the functional improvement observed in this model of PD.
背景与目标:
干细胞已被广泛认为能够替代许多疾病中丢失或受损的细胞,包括帕金森氏病(PD),在该疾病中黑质(SN)的神经元死亡而无法提供神经递质多巴胺(DA) ),到纹状体。我们报告说,未分化的人类神经干细胞(hNSCs)植入1-甲基-4-苯基-1,2,3,6-四氢吡啶处理的帕金森氏灵长类动物得以存活,迁移并通过行为改善定量评估了功能影响这种DA赤字模型,其中帕金森氏征与降低的DA水平直接相关。少量的hNSC后代分化为酪氨酸羟化酶(TH)和/或多巴胺转运蛋白(DAT)免疫阳性细胞,表明病变成年宿主SN内和周围的微环境仍然允许响应性祖细胞发展DA表型。发现大量不表达神经元或DA标记的hNSC衍生细胞沿着持续的黑纹状体路径排列,并与宿主细胞并列。这些表达DA保护因子的hNSCs处于良好位置,可以影响宿主TH细胞并介导其他稳态调节,这体现在恢复基线内源性神经元数与大小之比,保留现存宿主黑质纹状体回路和对α-突触核蛋白聚集的归一化作用。我们建议外源性hNSCs和病理宿主环境之间的相互交互的多种模式奠定了在这种PD模型中观察到的功能改善的基础。