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外2014 (IF 2.806)局灶性脑缺血大鼠模型中,rTMS通过调控MiR-25促进神经干细胞增值 Xiaolin Huang3.5TYRD-CCI
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Repetitive Transcranial Magnetic Stimulation Promotes Neural Stem Cell Proliferation via the Regulation of MiR-25 in a Rat Model of Focal Cerebral Ischemia Feng Guo1., Xiaohua Han1., Jinghui Zhang2, Xiuxiu Zhao1, Jicheng Lou3, Hong Chen1, Xiaolin Huang1* 1 Department of Rehabilitation Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, 2 Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China, 3 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Abstract Repetitive transcranial magnetic stimulation (rTMS) has increasingly been studied over the past decade to determine whether it has a therapeutic benefit on focal cerebral ischemia. However, the underlying mechanism of rTMS in this process remains unclear. In the current study, we investigated the effects of rTMS on the proliferation of adult neural stem cells (NSCs) and explored microRNAs (miRNAs) that were affected by rTMS. Our data showed that 10 Hz rTMS significantly increased the proliferation of adult NSCs after focal cerebral ischemia in the subventricular zone (SVZ), and the expression of miR-25 was obviously up-regulated in the ischemic cortex after rTMS. p57, an identified miR-25 target gene that regulates factors linked to NSC proliferation, was also evaluated, and it exhibited down-regulation. To further verify the role of miR-25, rats were injected with a single dose of antagomir-25 and were subjected to focal cerebral ischemia followed by rTMS treatment. The results confirmed that miR-25 could be repressed specifically and could drive the up-regulation of its target gene (p57), which resulted in the inhibition of adult NSC proliferation in the SVZ after rTMS. Thus, our studies strongly indicated that 10 Hz rTMS can promote the proliferation of adult NSCs in the SVZ after focal cerebral ischemia by regulating the miR-25/p57 pathway. Citation: Guo F, Han X, Zhang J, Zhao X, Lou J, et al. (2014) Repetitive Transcranial Magnetic Stimulation Promotes Neural Stem Cell Proliferation via the Regulation of MiR-25 in a Rat Model of Focal Cerebral Ischemia. PLoS ONE 9(10): e109267. doi:10.1371/journal.pone.0109267 Editor: Francis Szele, University of Oxford, United Kingdom Received April 18, 2014; Accepted September 8, 2014; Published October 10, 2014 Copyright: 2014 Guo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This study was supported by National Natural Science Foundation of China (Nos: 81071601, 81171858 and 81070986). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: xiaolinh2006@126.com . These authors contributed equally to this work. Introduction The risk of cerebrovascular disease increases substantially with age, making it the leading cause of death and severe long-term disability in humans [1]. The discovery of adult neural stem cells (NSCs) in 1992 brought new life to the treatment of cerebral vascular accidents [2]. It has been found that cerebral ischemia can activate the proliferation of dormant NSCs, accompanied by limited improvement to damaged neurological functions [3,4]. Thus, exploring methods to promote the proliferation of dormant NSCs after cerebral ischemia may be a promising strategy for ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS), a tech- nique used to repeatedly, non-invasively induce electric currents in a small area of the brain, has been widely applied in cerebral ischemia therapy recently. The latest research has reported that rTMS promotes the proliferation of adult NSCs in healthy rats; however, knowledge of the underlying mechanism has not yet been defined [5]. Additionally, little work has focused on the effects of rTMS on adult NSC proliferation in cerebral ischemia models, although the mechanism of rTMS in neurogenesis is critical for developing better therapies for cerebral ischemia patients. MicroRNAs (MiRNAs) are endogenous, short RNA sequences that have long been posited to be involved in neurogenesis and are thought to regulate the expression of target genes by base-pairing with specific binding sites located in the 39-untranslated region of the target mRNAs [6]. Because of the profound effects that rTMS has on gene expression, it is theoretically possible that they have the potential to regulate miRNA levels. Nevertheless, few reports have attempted to explain how rTMS regulates the proliferation of NSCs via miRNA. Recently, our group found that miR-25 increased significantly after 10 Hz rTMS treatment of cerebral ischemia in rats. This result suggested that 10 Hz rTMS played a regulatory role in the expression of miR-25. MiR-25 belongs to the miR-106b,25 cluster. This cluster is located within an intronic region of the Mcm7 gene and codes for three different mature miRNA species: miR-106b, miR-93 and miR-25. Emerging data have indicated that the miR-106b,25 cluster plays a critical role in adult NSC proliferation [7,8]. Additionally, Brett et al.’s group reported that the miR-106b,25 cluster could promote the proliferation of adult NSCs mainly due to miR-25 [9,10], which also appeared to be one of the strongly PLOS ONE | www.plosone.org 1 October 2014 | Volume 9 | Issue 10 | e109267

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