Ásgrímsdóttir Emilía Sif, Arenas Ernest
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Front Cell Dev Biol. 2020 Jun 25;8:463. doi: 10.3389/fcell.2020.00463. eCollection 2020.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that predominantly affects dopaminergic (DA) neurons of the substantia nigra. Current treatment options for PD are symptomatic and typically involve the replacement of DA neurotransmission by DA drugs, which relieve the patients of some of their motor symptoms. However, by the time of diagnosis, patients have already lost about 70% of their substantia nigra DA neurons and these drugs offer only temporary relief. Therefore, cell replacement therapy has garnered much interest as a potential treatment option for PD. Early studies using human fetal tissue for transplantation in PD patients provided proof of principle for cell replacement therapy, but they also highlighted the ethical and practical difficulties associated with using human fetal tissue as a cell source. In recent years, advancements in stem cell research have made human pluripotent stem cells (hPSCs) an attractive source of material for cell replacement therapy. Studies on how DA neurons are specified and differentiated in the developing mouse midbrain have allowed us to recapitulate many of the positional and temporal cues needed to generate DA neurons . However, little is known about the developmental programs that govern human DA neuron development. With the advent of single-cell RNA sequencing (scRNA-seq) and bioinformatics, it has become possible to analyze precious human samples with unprecedented detail and extract valuable high-quality information from large data sets. This technology has allowed the systematic classification of cell types present in the human developing midbrain along with their gene expression patterns. By studying human development in such an unbiased manner, we can begin to elucidate human DA neuron development and determine how much it differs from our knowledge of the rodent brain. Importantly, this molecular description of the function of human cells has become and will increasingly be a reference to define, evaluate, and engineer cell types for PD cell replacement therapy and disease modeling.
帕金森病（PD）是一种进行性神经退行性疾病，主要影响黑质中的多巴胺能（DA）神经元。目前针对PD的治疗方法是对症治疗，通常包括使用DA药物替代DA神经传递，这可缓解患者的一些运动症状。然而，在诊断时，患者已经损失了约70%的黑质DA神经元，而且这些药物只能提供暂时的缓解。因此，细胞替代疗法作为PD的一种潜在治疗选择引起了广泛关注。早期使用人类胎儿组织移植到PD患者体内的研究为细胞替代疗法提供了原理证明，但也凸显了使用人类胎儿组织作为细胞来源所涉及的伦理和实际困难。近年来，干细胞研究的进展使人类多能干细胞（hPSC）成为细胞替代疗法有吸引力的材料来源。对发育中的小鼠中脑DA神经元如何被指定和分化的研究，使我们能够重现生成DA神经元所需的许多位置和时间线索。然而，对于控制人类DA神经元发育的发育程序知之甚少。随着单细胞RNA测序（scRNA-seq）和生物信息学的出现，以前所未有的细节分析珍贵的人类样本并从大数据集中提取有价值的高质量信息成为可能。这项技术使我们能够对人类发育中的中脑存在的细胞类型及其基因表达模式进行系统分类。通过以这种无偏见的方式研究人类发育，我们可以开始阐明人类DA神经元的发育，并确定其与我们对啮齿动物大脑的了解有多大差异。重要的是，这种对人类细胞功能的分子描述已经并将越来越成为定义、评估和设计用于PD细胞替代疗法和疾病建模的细胞类型的参考。
