背景:散发性克雅氏病(sCJD),人类最常见的朊病毒病,是一种致命的神经退行性疾病,目前没有治疗选择。干细胞治疗神经退行性疾病正在成为一种可能的治疗选择。然而,虽然有一些其他神经退行性疾病如帕金森病的临床试验,到目前为止,朊病毒病细胞治疗的研究仅限于动物模型。
方法:这里,我们使用一种新的方法,利用人脑类器官模型研究sCJD细胞治疗.脑类器官可以感染sCJD病毒,使我们能够评估神经前体细胞(NPC)治疗如何影响sCJD的进展。在sCJD或模拟感染90天后,类器官要么用NPC接种,要么不接种,并监测细胞组成变化,感染后180天的朊病毒感染参数和神经电生理功能。
结果:我们的结果显示,NPCs整合到类器官中,导致神经元标记物的增加和细胞信号的变化,而与sCJD感染无关。虽然小,但意义重大,在接受NPCs的CJD感染的类器官中观察到蛋白酶抗性PrP沉积的减少,其他疾病相关参数变化最小.然而,NPCs对感染后的类器官功能有有益的影响.sCJD感染导致神经元尖峰率和平均突发尖峰率降低,指示动作电位降低。NPC播种将这些电生理参数恢复到未感染的对照水平。
结论:结合以前的动物研究,我们的结果支持细胞疗法可能对人类朊病毒疾病的治疗有一定的功能益处.
Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is a fatal neurodegenerative disease with currently no treatment options. Stem cell therapy for neurodegenerative diseases is emerging as a possible treatment option. However, while there are a few clinical trials for other neurodegenerative disorders such as Parkinson\'s disease, prion disease cell therapy research has so far been confined to animal models.
Here, we use a novel approach to study cell therapies in sCJD using a human cerebral organoid model. Cerebral organoids can be infected with sCJD prions allowing us to assess how neural precursor cell (NPC) therapy impacts the progression of sCJD. After 90 days of sCJD or mock infection, organoids were either seeded with NPCs or left unseeded and monitored for cellular composition changes, prion infection parameters and neuroelectrophysiological function at 180 days post-infection.
Our results showed NPCs integrated into organoids leading to an increase in neuronal markers and changes in cell signaling irrespective of sCJD infection. Although a small, but significant, decrease in protease-resistant PrP deposition was observed in the CJD-infected organoids that received the NPCs, other disease-associated parameters showed minimal changes. However, the NPCs had a beneficial impact on organoid function following infection. sCJD infection caused reduction in neuronal spike rate and mean burst spike rate, indicative of reduced action potentials. NPC seeding restored these electrophysiological parameters to the uninfected control level.
Together with the previous animal studies, our results support that cell therapy may have some functional benefit for the treatment of human prion diseases.