当前位置: X-MOL 学术J. Neurosci. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Understanding the Influence of Target Acquisition on Survival, Integration, and Phenotypic Maturation of Dopamine Neurons within Stem Cell-Derived Neural Grafts in a Parkinson's Disease Model
Journal of Neuroscience ( IF 5.3 ) Pub Date : 2022-06-22 , DOI: 10.1523/jneurosci.2431-21.2022
Niamh Moriarty 1 , Jessica A Kauhausen 1 , Chiara Pavan 1 , Cameron P J Hunt 1 , Isabelle R de Luzy 1 , Vanessa Penna 1 , Charlotte M Ermine 1 , Lachlan H Thompson 2 , Clare L Parish 2
Affiliation  

Midbrain dopaminergic (DA) neurons include many subtypes characterized by their location, connectivity and function. Surprisingly, mechanisms underpinning the specification of A9 neurons [responsible for motor function, including within ventral midbrain (VM) grafts for treating Parkinson's disease (PD)] over adjacent A10, remains largely speculated. We assessed the impact of synaptic targeting on survival, integration, and phenotype acquisition of dopaminergic neurons within VM grafts generated from fetal tissue or human pluripotent stem cells (PSCs). VM progenitors were grafted into female mice with 6OHDA-lesions of host midbrain dopamine neurons, with some animals also receiving intrastriatal quinolinic acid (QA) injections to ablate medium spiny neurons (MSN), the A9 neuron primary target. While loss of MSNs variably affected graft survival, it significantly reduced striatal yet increased cortical innervation. Consequently, grafts showed reduced A9 and increased A10 specification, with more DA neurons failing to mature into either subtype. These findings highlight the importance of target acquisition on DA subtype specification during development and repair.

SIGNIFICANCE STATEMENT Parish and colleagues highlight, in a rodent model of Parkinson's disease (PD), the importance of synaptic target acquisition in the survival, integration and phenotypic specification of grafted dopamine neurons derived from fetal tissue and human stem cells. Ablation of host striatal neurons resulted in reduced dopamine neuron survival within grafts, re-routing of dopamine fibers from striatal to alternate cortical targets and a consequential reduced specification of A9 dopamine neurons (the subpopulation critical for restoration of motor function) and increase in A10 DA neurons.



中文翻译:

了解目标获取对帕金森病模型中干细胞衍生神经移植物中多巴胺神经元存活、整合和表型成熟的影响

中脑多巴胺能 (DA) 神经元包括许多以其位置、连接性和功能为特征的亚型。令人惊讶的是,支持 A9 神经元 [负责运动功能,包括用于治疗帕金森病 (PD) 的腹侧中脑 (VM) 移植物内] 超过相邻 A10 的规范的机制仍然在很大程度上被推测。我们评估了突触靶向对胎儿组织或人类多能干细胞 (PSC) 产生的 VM 移植物中多巴胺能神经元的存活、整合和表型获取的影响。VM 祖细胞被移植到具有宿主中脑多巴胺神经元 6OHDA 损伤的雌性小鼠体内,一些动物还接受纹状体内喹啉酸 (QA) 注射以消融中型多刺神经元 (MSN),这是 A9 神经元的主要目标。虽然 MSN 的丢失会不同程度地影响移植物的存活,它显着减少了纹状体,但增加了皮质神经支配。因此,移植物显示 A9 减少和 A10 规格增加,更多的 DA 神经元未能成熟为任一亚型。这些发现强调了在开发和修复过程中目标获取对 DA 亚型规范的重要性。

重要性声明Parish 及其同事强调,在帕金森病 (PD) 的啮齿动物模型中,突触目标获取在源自胎儿组织和人类干细胞的移植多巴胺神经元的存活、整合和表型规范中的重要性。宿主纹状体神经元的消融导致移植物内多巴胺神经元存活率降低,多巴胺纤维从纹状体重新路由到交替的皮质目标,随之而来的是 A9 多巴胺神经元(对恢复运动功能至关重要的亚群)的规格降低和 A10 DA 的增加神经元。

更新日期:2022-06-23
down
wechat
bug