title: Adipose-Derived Stem Cells Induce Angiogenesis via Microvesicle Transport of miRNA-31.
abstract: Cell secretion is an important mechanism for stem cell-based therapeutic angiogenesis, along with cell differentiation to vascular endothelial cells or smooth muscle cells. Cell-released microvesicles (MVs) have been recently implicated to play an essential role in intercellular communication. The purpose of this study was to explore the potential effects of stem cell-released MVs in proangiogenic therapy. We observed for the first time that MVs were released from adipose-derived stem cells (ASCs) and were able to increase the migration and tube formation of human umbilical vein endothelial cells (HUVECs). Endothelial differentiation medium (EDM) preconditioning of ASCs upregulated the release of MVs and enhanced the angiogenic effect of the released MVs in vitro. RNA analysis revealed that microRNA was enriched in ASC-released MVs and that the level of microRNA-31 (miR-31) in MVs was notably elevated upon EDM-preconditioning of MV-donor ASCs. Further studies exhibited that miR-31 in MVs contributed to the migration and tube formation of HUVECs, microvessel outgrowth of mouse aortic rings, and vascular formation of mouse Matrigel plugs. Moreover, factor-inhibiting HIF-1, an antiangiogenic gene, was identified as the target of miR-31 in HUVECs. Our findings provide the first evidence that MVs from ASCs, particularly from EDM-preconditioned ASCs, promote angiogenesis and the delivery of miR-31 may contribute the proangiogenic effect.
  
  
  CONCLUSIONS
  This study provides the evidence that microvesicles (MVs) from adipose-derived stem cells (ASCs), particularly from endothelial differentiation medium (EDM)-preconditioned ASCs, promote angiogenesis. An underlying mechanism of the proangiogenesis may be the delivery of microRNA-31 via MVs from ASCs to vascular endothelial cells in which factor-inhibiting HIF-1 is targeted and suppressed. The study findings reveal the role of MVs in mediating ASC-induced angiogenesis and suggest a potential MV-based angiogenic therapy for ischemic diseases.
authors.affiliation: Division of Cardiology, The First Affiliated Hospital, Nanchang University, Nanchang, People's Republic of China Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Kang
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Tia M
authors.initials: TM
authors.lastname: Jones
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Clayton
authors.initials: C
authors.lastname: Naddell
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Methode
authors.initials: M
authors.lastname: Bacanamwo
authors.affiliation: Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.affiliation: Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Winston E
authors.initials: WE
authors.lastname: Thompson
authors.affiliation: Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia, USA.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Bond
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia, USA Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia, USA dliu@msm.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D053687:Adult Stem Cells / Q000166:cytology / Q000502:physiology*; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055806:Microvessels / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000235:genetics
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; C539917:Mirn31 microRNA, mouse
keywords: Adipose stem cell; Angiogenesis; Endothelial cell; Microvesicle; miRNA