title: MiR-211/STAT5A Signaling Modulates Migration of Mesenchymal Stem Cells to Improve its Therapeutic Efficacy.
abstract: Our previous study showed that the therapeutic effects of mesenchymal stem cells (MSCs) transplantation were improved by enhancing migration. MicroRNA-211 (miR-211) can modulate the migratory properties of some cell types by mechanisms that are not fully understood. This study was designed to investigate a possible role for miR-211 in MSC migration, and whether genetic manipulation of miR-211 in MSCs could be used to enhance its beneficial effects of cell transplantation. Transwell assays confirmed that MSCs migration of was significantly impaired by miR-211 knockdown but enhanced by miR-211 overexpression. MiR-211 overexpressing MSCs also exhibited significantly increased cell engraftment in the peri-infarct areas of female rat hearts 2 days after intravenous transplantation of male MSCs as shown by GFP tracking and SYR gene quantification. This conferred a significant decrease in infarct size and improved cardiac performance. By using a loss or gain of gene function approach, we demonstrated that miR-211 targeted STAT5A to modulate MSCs migration, possibly by interacting with MAPK signaling. Furthermore, the beneficial effects of miR-211 overexpression in MSCs were abolished by simultaneous overexpression of STAT5A whereas the negative effects of miR-211 silencing on MSC migration were rescued by simultaneous downregulation of STAT5A. Finally, using ChIP-PCR and luciferase assays, we provide novel evidence that STAT3 can directly bind to promoter elements that activate miR-211 expression. STAT3/miR-211/STAT5A signaling plays a key role in MSCs migration. Intravenous infusion of genetically modified miR-211 overexpressing MSCs conveys enhanced protection from adverse post-MI remodeling compared with unmodified MSCs. Stem Cells 2016;34:1846-1858.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Kan
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Yinchuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Molecular and Cellular Pharmacology, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China.|Provincial Key Laboratory of Cardiovascular Research, Hangzhou, People's Republic of China.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics; D002465:Cell Movement; D016922:Cellular Senescence / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy; D017207:Rats, Sprague-Dawley; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C549405:MIRN211 microRNA, human; C000608866:MIRN211 microRNA, rat; D035683:MicroRNAs; D050799:STAT5 Transcription Factor
keywords: Mesenchymal stem cells; MicroRNA-211; Migration; Myocardial infarction; Retention; STAT5A