Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, and Lund Stem Cell Centre, Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
Cells. 2021 Jun 1;10(6):1366. doi: 10.3390/cells10061366.
Human midbrain dopamine (DA) neurons are a heterogeneous group of cells that share a common neurotransmitter phenotype and are in close anatomical proximity but display different functions, sensitivity to degeneration, and axonal innervation targets. The A9 DA neuron subtype controls motor function and is primarily degenerated in Parkinson's disease (PD), whereas A10 neurons are largely unaffected by the condition, and their dysfunction is associated with neuropsychiatric disorders. Currently, DA neurons can only be reliably classified on the basis of topographical features, including anatomical location in the midbrain and projection targets in the forebrain. No systematic molecular classification at the genome-wide level has been proposed to date. Although many years of scientific efforts in embryonic and adult mouse brain have positioned us to better understand the complexity of DA neuron biology, many biological phenomena specific to humans are not amenable to being reproduced in animal models. The establishment of human cell-based systems combined with advanced computational single-cell transcriptomics holds great promise for decoding the mechanisms underlying maturation and diversification of human DA neurons, and linking their molecular heterogeneity to functions in the midbrain. Human pluripotent stem cells have emerged as a useful tool to recapitulate key molecular features of mature DA neuron subtypes. Here, we review some of the most recent advances and discuss the current challenges in using stem cells, to model human DA biology. We also describe how single cell RNA sequencing may provide key insights into the molecular programs driving DA progenitor specification into mature DA neuron subtypes. Exploiting the state-of-the-art approaches will lead to a better understanding of stem cell-derived DA neurons and their use in disease modeling and regenerative medicine.
人类中脑多巴胺 (DA) 神经元是一组具有共同神经递质表型的异质性细胞，它们在解剖学上非常接近，但具有不同的功能、对变性的敏感性以及轴突支配的靶标。A9 DA 神经元亚型控制运动功能，主要在帕金森病 (PD) 中退化，而 A10 神经元在很大程度上不受该疾病影响，其功能障碍与神经精神疾病有关。目前，只能基于拓扑特征（包括中脑的解剖位置和前脑的投射靶标）可靠地对 DA 神经元进行分类。迄今为止，尚未提出基于全基因组水平的系统分子分类。尽管多年来在胚胎和成年小鼠大脑中的科学努力使我们能够更好地理解 DA 神经元生物学的复杂性，但许多特定于人类的生物学现象无法在动物模型中重现。结合先进的计算单细胞转录组学的人类基于细胞的系统的建立为解码人类 DA 神经元成熟和多样化的机制以及将其分子异质性与中脑的功能联系起来提供了很大的希望。人类多能干细胞已成为重现成熟 DA 神经元亚型关键分子特征的有用工具。在这里，我们回顾了一些最新进展，并讨论了使用干细胞来模拟人类 DA 生物学的当前挑战。我们还描述了单细胞 RNA 测序如何为驱动 DA 祖细胞特化成为成熟 DA 神经元亚型的分子程序提供关键见解。利用最先进的方法将有助于更好地理解基于干细胞的 DA 神经元及其在疾病建模和再生医学中的应用。
