Silencing of circular RNA HIPK2 in neural stem cells enhances functional recovery following ischaemic stroke
Guangtian Wang,
Bing Han,
Ling Shen,
Shusheng Wu,
Li Yang,
Jiefeng Liao,
Fangfang Wu,
Mingyue Li,
Shuo Leng,
Fengchao Zang,
Yuan Zhang,
Ying Bai,
Yu Mao,
Bo Chen,
Honghong Yao
Affiliations
Guangtian Wang
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Bing Han
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Ling Shen
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Shusheng Wu
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Li Yang
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Jiefeng Liao
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Fangfang Wu
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Mingyue Li
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Shuo Leng
Department of Radiology, School of Medicine, Southeast University, Nanjing 210009, China
Fengchao Zang
Department of Radiology, School of Medicine, Southeast University, Nanjing 210009, China
Yuan Zhang
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Ying Bai
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China
Yu Mao
State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Sciences & Medical Engineering, Southeast University, Nanjing 210009, China
Bo Chen
Materials Science and Devices Institute, Suzhou University of Science and Technology, Suzhou 215009, China
Honghong Yao
Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China; Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210009, China; Co-innovation Centre of Neuroregeneration, Nantong University, Nantong 226001, China; Corresponding author at: Department of Pharmacology, School of Medicine, Southeast University, Nanjing 210009, China.
Background: 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. Methods: 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. Findings: 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. Interpretations: Si-circHIPK2 regulates NSC differentiation, and microinjection of si-circHIPK2-NSCs exhibits a promising therapeutic strategy to neuroprotection and functional recovery after stroke. Funding: 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. Keywords: Neural stem cells, Differentiation, circHIPK2, Stroke, Functional recovery
