Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons.
Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons.
复制标题
血管源性神经元和SerpinE1调节人干细胞源性中间神经元的切向迁移并加速其功能成熟
作者：
Genestine M;Ambriz D;Crabtree GW;Dummer P;Molotkova A;Quintero M;Mela A;Biswas S;Feng H;Zhang C;Canoll P;Hargus G;Agalliu D;Gogos JA;Au E
皮质中间神经元在整个新皮质建立抑制性微回路，并且它们的功能障碍与癫痫和神经精神疾病有关。在发育过程中，中间神经元从远端祖细胞区域迁移到新皮层--这一过程在人类中的发生速度比在小鼠中慢。在这项研究中，我们试图确定调节两个物种中间神经元成熟速率的因素。使用胚胎小鼠发育作为模型系统，我们发现启动中间神经元迁移的过程受到内侧神经节隆起（MGE）（中间神经元祖细胞结构域）的血管的调节。我们确定了两个内皮细胞衍生的旁分泌因子，E2和SerpinE 1，增强小鼠MGE外植体和器官型培养物中的中间神经元迁移。此外，预处理的人干细胞衍生的interneurons（hSC-interneurons）与SerpinE 1移植到新生小鼠皮质增强其迁移和宿主皮质中的形态学阐述之前。此外，与对照组相比，经β-内酰胺酶和丝氨酸蛋白酶抑制剂E1处理的hSC-中间神经元也表现出更成熟的电生理学特征。总之，我们的研究表明，中枢神经系统血管在调节小鼠和人类中间神经元发育成熟中起着关键作用。
Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex – a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.
影响因子：
3.7
作者：
Turakainen H;Saarimäki-Vire J;Sinjushina N;Partanen J;Savilahti H
通讯作者：
Savilahti H