Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 308232, Singapore.
Interdisciplinary Graduate Programme (IGP-Neuroscience), Nanyang Technological University, Singapore 639798, Singapore.
Int J Mol Sci. 2023 Jan 28;24(3):2523. doi: 10.3390/ijms24032523.
Parkinson's Disease (PD) is a prevalent neurodegenerative disorder that is characterized pathologically by the loss of A9-specific dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD is currently unresolved, and the disease remains incurable. This, in part, is due to the lack of an experimental disease model that could faithfully recapitulate the features of human PD. However, the recent advent of induced pluripotent stem cell (iPSC) technology has allowed PD models to be created from patient-derived cells. Indeed, DA neurons from PD patients are now routinely established in many laboratories as monolayers as well as 3D organoid cultures that serve as useful toolboxes for understanding the mechanism underlying PD and also for drug discovery. At the same time, the iPSC technology also provides unprecedented opportunity for autologous cell-based therapy for the PD patient to be performed using the patient's own cells as starting materials. In this review, we provide an update on the molecular processes underpinning the development and differentiation of human pluripotent stem cells (PSCs) into midbrain DA neurons in both 2D and 3D cultures, as well as the latest advancements in using these cells for drug discovery and regenerative medicine. For the novice entering the field, the cornucopia of differentiation protocols reported for the generation of midbrain DA neurons may seem daunting. Here, we have distilled the essence of the different approaches and summarized the main factors driving DA neuronal differentiation, with the view to provide a useful guide to newcomers who are interested in developing iPSC-based models of PD.
帕金森病（PD）是一种常见的神经退行性疾病，其病理学特征是中脑黑质致密部（SNpc）中 A9 特异性多巴胺能（DA）神经元的丧失。尽管进行了深入研究，但 PD 的病因目前仍未解决，而且这种疾病仍然无法治愈。部分原因是缺乏能够忠实地再现人类 PD 特征的实验疾病模型。然而，最近诱导多能干细胞（iPSC）技术的出现使得能够从患者来源的细胞中创建 PD 模型。事实上，来自 PD 患者的 DA 神经元现在在许多实验室中作为单层以及 3D 类器官培养物常规建立，这些培养物作为理解 PD 发病机制以及药物发现的有用工具包。同时，iPSC 技术还为 PD 患者的自体细胞为基础的治疗提供了前所未有的机会，使用患者自身的细胞作为起始材料。在这篇综述中，我们提供了最新的关于人类多能干细胞（PSCs）在 2D 和 3D 培养物中向中脑 DA 神经元发育和分化的分子过程的更新信息，以及使用这些细胞进行药物发现和再生医学的最新进展。对于刚进入该领域的新手来说，用于产生中脑 DA 神经元的分化方案的大量报道可能看起来令人生畏。在这里，我们提炼了不同方法的本质，并总结了驱动 DA 神经元分化的主要因素，以期为有兴趣开发基于 iPSC 的 PD 模型的新入门者提供有用的指南。
