Background:Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson’s disease (PD) and they provide the option of using the patient’s own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD. Objective:To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control. Methods:Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo. Results:Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line. Conclusion:This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.

中文翻译：

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源自 α-突触核蛋白三重患者的移植物介导功能恢复但在帕金森病的 6-OHDA 模型中发展疾病相关病理

背景：人类诱导多能干细胞 (hiPSC) 已被提议作为帕金森病 (PD) 细胞替代疗法的替代来源，并且它们提供了使用患者自身细胞的选择。一些研究调查了在临床前模型中移植患者来源的多巴胺能 (DA) 神经元；然而，对于源自 PD 患者的移植物的长期完整性和功能知之甚少。目的：使用临床级人类胚胎干细胞 (hESC) 系 (RC17) 作为参考对照，评估源自具有 α-突触核蛋白基因三倍 (AST18) 的患者 hiPSC 系的 DA 神经元移植物的活力和功能。方法：使用已建立的 GMP 协议将细胞分化为腹侧中脑 (VM) 模式的 DA 祖细胞。然后将祖细胞在体外最终分化为成熟的 DA 神经元，或移植到 6-羟基多巴胺 (6-OHDA) 损伤的大鼠中，并在体内评估它们的存活、成熟、功能和发生 α-突触核蛋白相关病理的倾向。结果：两种细胞系都在体外产生了具有 DA 特性的功能性神经元。AST18 衍生的 VM 祖细胞在移植后存活并成熟为类似于 RC17 细胞的富含神经元的移植物。24 周后，两种细胞系都产生了介导全功能恢复的富含 DA 的移植物；然而，仅在源自 α-突触核蛋白三倍体患者系的移植物中观察到病理变化。结论：该数据显示了 PD 的 6-OHDA 模型中家族性 PD 患者来源细胞的存活和功能恢复的原理证明。然而，