Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models

doi:10.1161/CIRCULATIONAHA.120.045765

	Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models
	Yang, Li 1; Han, Bing 1; Zhang, Zhiting 2,8,13,14; Wang, Shuguo 9; Bai, Ying 1; Zhang, Yuan 1; Tang, Ying 1; Du, Lingli 2; Xu, Ling 2; Wu, Fangfang 1
刊名	CIRCULATION
	2020-08-11
卷号	142 期号:6 页码:556-574
关键词	circular RNA extracellular vesicles MeCP2 protein neuronal plasticity primate stroke
ISSN号	0009-7322
DOI	10.1161/CIRCULATIONAHA.120.045765
通讯作者	Wang, Jianhong(wangjh@mail.kiz.ac.cn) ; Yao, Honghong(yaohh@seu.edu.cn)
英文摘要	Background: Stroke is a leading cause of adult disability that can severely compromise the quality of life of patients, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNA) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of the potential therapeutic roles for circRNAs. Methods: Circular RNA SCMH1 (circSCMH1) was screened from the plasma of patients with acute ischemic stroke by using circRNA microarrays. Engineered rabies virus glycoprotein-circSCMH1-extracellular vesicles were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-sequencing data combined with transcriptional profiling were used to identify downstream targets of circSCMH1. Results: CircSCMH1 levels were significantly decreased in the plasma of patients with acute ischemic stroke, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery after stroke in both mice and monkeys, and we discovered that circSCMH1 enhanced the neuronal plasticity and inhibited glial activation and peripheral immune cell infiltration. CircSCMH1 binds mechanistically to the transcription factor MeCP2 (methyl-CpG binding protein 2), thereby releasing repression of MeCP2 target gene transcription. Conclusions: Rabies virus glycoprotein-circSCMH1-extracellular vesicles afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve poststroke outcomes.
资助项目	National Key Research and Development Program of China[2018YFC1313803] ; National Key Research and Development Program of China[2017YFA0104303] ; National Natural Science Foundation of China[81473190] ; National Natural Science Foundation of China[81673410] ; National Natural Science Foundation of China[81761138048] ; Jiangsu Specially Appointed Professor ; Major State Basic Research Development Program of China (973 Program)[2013CB733800] ; Major State Basic Research Development Program of China (973 Program)[2013CB733803] ; National Science and Technology Major Project[2020 ZX09201015] ; CAMS Innovation Fund for Medical Sciences[2016-I2M-1-004] ; Yunnan Key Program of Science and Technology[2017FA042] ; National Science Foundation of China[31771194] ; National Science Foundation of China[31571109]
WOS关键词	STROMAL CELLS ; BRAIN-INJURY ; MOUSE-BRAIN ; PHOSPHORYLATION ; NEUROPLASTICITY ; INHIBITION ; EXOSOMES ; THERAPY
WOS研究方向	Cardiovascular System & Cardiology
语种	英语
出版者	LIPPINCOTT WILLIAMS & WILKINS
WOS记录号	WOS:000562734100014
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292406]
专题	中国科学院上海药物研究所
通讯作者	Wang, Jianhong; Yao, Honghong
作者单位	1.Southeast Univ, Dept Pharmacol, Med Sch, Nanjing 210009, Jiangsu, Peoples R China 2.Chinese Acad Sci, Kunming Inst Zool, Natl Res Facil Phenotyp & Genet Anal Model Anim P, Kunming 650223, Yunnan, Peoples R China 3.Southeast Univ, Inst Neuropsychiat, Dept Neurol, Affiliated ZhongDa Hosp, Nanjing, Peoples R China 4.Southeast Univ, Inst Life Sci, Key Lab Dev Genes & Human Dis, Nanjing, Peoples R China 5.Chinese Acad Sci, Kunming Inst Zool, Natl Resource Ctr Nonhuman Primates, Kunming Primate Res Ctr, Kunming, Yunnan, Peoples R China 6.Chinese Acad Sci, Kunming Inst Zool, Key Lab Anim Models & Human Dis Mech, Chinese Acad Sci & Yunnan Prov, Kunming, Yunnan, Peoples R China 7.Chinese Acad Sci, Kunming Inst Zool, KIZ CUHK Joint Lab Bioresources & Mol Res Common, Kunming, Yunnan, Peoples R China 8.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei, Peoples R China 9.Kunming Med Univ, Dept Neurosurg, Affiliat Hosp 1, Kunming, Yunnan, Peoples R China 10.Jiangsu Prov Hosp, Emergency Dept, Nanjing, Peoples R China
推荐引用方式 GB/T 7714	Yang, Li,Han, Bing,Zhang, Zhiting,et al. Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models[J]. CIRCULATION,2020,142(6):556-574.
APA	Yang, Li.,Han, Bing.,Zhang, Zhiting.,Wang, Shuguo.,Bai, Ying.,...&Yao, Honghong.(2020).Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.CIRCULATION,142(6),556-574.
MLA	Yang, Li,et al."Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models".CIRCULATION 142.6(2020):556-574.