Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China.
Department of Radiology, School of Medicine, Southeast University, Nanjing 210009, China.
EBioMedicine. 2020 Feb;52:102660. doi: 10.1016/j.ebiom.2020.102660. Epub 2020 Feb 12.
Circular RNAs (circRNAs) have been reported to be involved in central nervous system (CNS) diseases and to have a close connection with neuronal development. However, the role of circRNAs in neural stem cell (NSC) differentiation and the treatment of ischaemic stroke remains unknown.
Ischaemic stroke was induced in mice using transient middle cerebral artery occlusion (tMCAO). NSCs were transducted with circHIPK2 siRNA (si-circHIPK2-NSCs) or vehicle control (si-circCon-NSCs) and microinjected into lateral ventricle of brain at 7 d post-tMCAO. Magnetic resonance imaging (MRI) was used to detect brain damage, and functional deficits were evaluated with sensorimotor behavioural tests. The distribution of the transplanted NSCs was investigated by near-infrared fluorescence imaging (NIF) and immunofluorescence. The neural plasticity of si-circHIPK2-NSCs was verified by western blot and immunofluorescence in vivo and in vitro.
We investigated the role of circHIPK2 in NCS differentiation. In vitro, silencing of circHIPK2 facilitated NSCs directionally differentiated to neurons but had no effect on the differentiation to astrocytes. In vivo, microinjected NSCs could migrate to the ischaemic hemisphere after stroke induction. Si-circHIPK2-NSCs increased neuronal plasticity in the ischaemic brain, conferred long-lasting neuroprotection, and significantly reduced functional deficits.
Si-circHIPK2 regulates NSC differentiation, and microinjection of si-circHIPK2-NSCs exhibits a promising therapeutic strategy to neuroprotection and functional recovery after stroke.
The National Key Research and Development Program of China; the International Cooperation and Exchange of the National Natural Science Foundation of China; the National Natural Science Foundation of China; the Jiangsu Innovation & Entrepreneurship Team Program.
环状 RNA（circRNAs）已被报道参与中枢神经系统（CNS）疾病，并与神经元发育密切相关。然而，circRNAs 在神经干细胞（NSC）分化和缺血性中风治疗中的作用尚不清楚。
采用短暂性大脑中动脉闭塞（tMCAO）诱导小鼠缺血性中风。在 tMCAO 后 7 天，将 NSCs 转导 circHIPK2 siRNA（si-circHIPK2-NSCs）或载体对照（si-circCon-NSCs）并微注射到侧脑室。磁共振成像（MRI）用于检测脑损伤，感觉运动行为测试用于评估功能缺陷。通过近红外荧光成像（NIF）和免疫荧光检测移植 NSCs 的分布。通过体内和体外 Western blot 和免疫荧光验证 si-circHIPK2-NSCs 的神经可塑性。
我们研究了 circHIPK2 在 NCS 分化中的作用。体外，沉默 circHIPK2 促进 NSCs 定向分化为神经元，但对分化为星形胶质细胞没有影响。体内，中风诱导后，注射的 NSCs 可迁移到缺血半球。Si-circHIPK2-NSCs 增加了缺血大脑中的神经元可塑性，提供了持久的神经保护，并显著减少了功能缺陷。
Si-circHIPK2 调节 NSC 分化，微注射 si-circHIPK2-NSCs 是一种有前途的治疗策略，可在中风后实现神经保护和功能恢复。
国家重点研发计划；国家自然科学基金国际合作与交流项目；国家自然科学基金；江苏省创新创业团队计划。
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