title: Involvement of miR-34c in high glucose-insulted mesenchymal stem cells leads to inefficient therapeutic effect on myocardial infarction.
abstract: High glucose-insulted bone marrow-derived mesenchymal stem cells (BMCs) showed impaired angiogenesis along with downregulation of stem cell factor (SCF). This study was designed to determine the involvement of microRNAs (miR), which are actively involved in the physiological function of stem cells. We observed that miR-34c was significantly induced by high glucose treatment and blunted tube formation of BMCs. Stem cell factor (SCF) was confirmed as a target of miR-34c by 3'-UTR promoter analysis and Western blot. SCF knockdown by siRNA induced Krüppel-like factor 4 (KLF4) and resulted in the blockade of angiogenesis of BMCs. Sequentially, KLF4 overexpression completely blocked tube formation through inducing PAI-1 (plasminogen activator inhibitor-1). To study the action of miR-34c in terms of the therapeutic potential of BMCs, myocardial infarction (MI) was induced by ligation of the coronary artery in nude mice, BMCs transfected with miR-control or miR-34c were injected into the infarcted myocardium 7 days later, and histological studies were performed 2 weeks later. Cardiac fibrosis was 18.24±4.7% in the miR-34c-BMC group and 10.01±0.2% in the miR-control-BMC group (p<0.05). Cardiac function and vessel density were decreased in the miR-34c-BMC group compared with the miR-con-BMC group. Particularly, miR-34c-BMCs failed to incorporate into vessels. Our results show that the angiogenic activity of BMCs is finely regulated by the miR-34c-SCF-KLF4 axis, which is a potent translational target for optimizing the therapeutic activity of autologous BMCs for cardiac repair.
authors.affiliation: Department of Molecular Medicine, Graduate School, Chonnam National University, Gwangju, Republic of Korea; Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Wan Seok
authors.initials: WS
authors.lastname: Kang
authors.affiliation: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Moon Hwa
authors.initials: MH
authors.lastname: Hong
authors.affiliation: Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea.
authors.forename: Nakwon
authors.initials: N
authors.lastname: Choe
authors.affiliation: Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
authors.affiliation: Department of Cardiology, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Hae Chang
authors.initials: HC
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jeehoon
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul 110-744, Republic of Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Cardiology, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea.
authors.forename: Myung Ho
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea; Biomedical Research Institute, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea. Electronic address: retissue@jnu.ac.kr.
authors.forename: Yong Sook
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea; Department of Cardiology, Chonnam National University Hospital, Gwangju 501-757, Republic of Korea. Electronic address: cecilyk@hanmail.net.
authors.forename: Youngkeun
authors.initials: Y
authors.lastname: Ahn
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000601:surgery; D015536:Down-Regulation; D005355:Fibrosis / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019089:Stem Cell Factor / Q000096:biosynthesis / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C066855:HGF protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; C051321:SERPINE1 protein, human; D019089:Stem Cell Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D005947:Glucose
keywords: Angiogenesis; High glucose; Mesenchymal stem cells; MiR-34c; Stem cell factor