title: Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology.
abstract: BACKGROUND
  Myocardial infarction is a leading cause of death in developed nations, and there remains a need for cardiac therapeutic systems that mitigate tissue damage. Cardiac progenitor cells (CPCs) and other stem cell types are attractive candidates for treatment of myocardial infarction; however, the benefit of these cells may be as a result of paracrine effects.
  
  
  OBJECTIVE
  We tested the hypothesis that CPCs secrete proregenerative exosomes in response to hypoxic conditions.
  
  
  RESULTS
  The angiogenic and antifibrotic potential of secreted exosomes on cardiac endothelial cells and cardiac fibroblasts were assessed. We found that CPC exosomes secreted in response to hypoxia enhanced tube formation of endothelial cells and decreased profibrotic gene expression in TGF-β-stimulated fibroblasts, indicating that these exosomes possess therapeutic potential. Microarray analysis of exosomes secreted by hypoxic CPCs identified 11 miRNAs that were upregulated compared with exosomes secreted by CPCs grown under normoxic conditions. Principle component analysis was performed to identify miRNAs that were coregulated in response to distinct exosome-generating conditions. To investigate the cue-signal-response relationships of these miRNA clusters with a physiological outcome of tube formation or fibrotic gene expression, partial least squares regression analysis was applied. The importance of each up- or downregulated miRNA on physiological outcomes was determined. Finally, to validate the model, we delivered exosomes after ischemia-reperfusion injury. Exosomes from hypoxic CPCs improved cardiac function and reduced fibrosis.
  
  
  CONCLUSIONS
  These data provide a foundation for subsequent research of the use of exosomal miRNA and systems biology as therapeutic strategies for the damaged heart.
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Warren D
authors.initials: WD
authors.lastname: Gray
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Kristin M
authors.initials: KM
authors.lastname: French
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Shohini
authors.initials: S
authors.lastname: Ghosh-Choudhary
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Maxwell
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Milton E
authors.initials: ME
authors.lastname: Brown
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Manu O
authors.initials: MO
authors.lastname: Platt
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.).
authors.forename: Charles D
authors.initials: CD
authors.lastname: Searles
authors.affiliation: From the The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA (W.D.G., K.M.F., S.G.-C., J.T.M., M.E.B., M.O.P., M.E.D.); Division of Cardiology, Emory University School of Medicine, Atlanta, GA (W.D.G., C.D.S., M.E.D.); Atlanta Veterans Administration Medical Center, Decatur, GA (C.D.S.); and Emory+Children's Center for Cardiovascular Biology, Emory University School of Medicine and Children's Healthcare of Atlanta, GA (M.E.D.). michael.davis@bme.emory.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015687:Cell Hypoxia / Q000502:physiology; D055354:Exosomes / Q000502:physiology*; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000502:physiology*; D049490:Systems Biology / Q000379:methods*
chemical_list: D035683:MicroRNAs
keywords: exosomes; microRNA; systems biology