title: Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132.
abstract: BACKGROUND
  Pericytes are key regulators of vascular maturation, but their value for cardiac repair remains unknown.
  
  
  OBJECTIVE
  We investigated the therapeutic activity and mechanistic targets of saphenous vein-derived pericyte progenitor cells (SVPs) in a mouse myocardial infarction (MI) model.
  
  
  RESULTS
  SVPs have a low immunogenic profile and are resistant to hypoxia/starvation (H/S). Transplantation of SVPs into the peri-infarct zone of immunodeficient CD1/Foxn-1(nu/nu) or immunocompetent CD1 mice attenuated left ventricular dilatation and improved ejection fraction compared to vehicle. Moreover, SVPs reduced myocardial scar, cardiomyocyte apoptosis and interstitial fibrosis, improved myocardial blood flow and neovascularization, and attenuated vascular permeability. SVPs secrete vascular endothelial growth factor A, angiopoietin-1, and chemokines and induce an endogenous angiocrine response by the host, through recruitment of vascular endothelial growth factor B expressing monocytes. The association of donor- and recipient-derived stimuli activates the proangiogenic and prosurvival Akt/eNOS/Bcl-2 signaling pathway. Moreover, microRNA-132 (miR-132) was constitutively expressed and secreted by SVPs and remarkably upregulated, together with its transcriptional activator cyclic AMP response element-binding protein, on stimulation by H/S or vascular endothelial growth factor B. We next investigated if SVP-secreted miR-132 acts as a paracrine activator of cardiac healing. In vitro studies showed that SVP conditioned medium stimulates endothelial tube formation and reduces myofibroblast differentiation, through inhibition of Ras-GTPase activating protein and methyl-CpG-binding protein 2, which are validated miR-132 targets. Furthermore, miR-132 inhibition by antimiR-132 decreased SVP capacity to improve contractility, reparative angiogenesis, and interstitial fibrosis in infarcted hearts.
  
  
  CONCLUSIONS
  SVP transplantation produces long-term improvement of cardiac function through a novel paracrine mechanism involving the secretion of miR-132 and inhibition of its target genes.
authors.affiliation: University of Bristol, Bristol Royal Infirmary-level 7, United Kingdom.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Katare
authors.forename: Federica
authors.initials: F
authors.lastname: Riu
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mitchell
authors.forename: Miriam
authors.initials: M
authors.lastname: Gubernator
authors.forename: Paola
authors.initials: P
authors.lastname: Campagnolo
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Cui
authors.forename: Orazio
authors.initials: O
authors.lastname: Fortunato
authors.forename: Elisa
authors.initials: E
authors.lastname: Avolio
authors.forename: Daniela
authors.initials: D
authors.lastname: Cesselli
authors.forename: Antonio Paolo
authors.initials: AP
authors.lastname: Beltrami
authors.forename: Gianni
authors.initials: G
authors.lastname: Angelini
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000378:metabolism; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020286:Pericytes / Q000378:metabolism / Q000637:transplantation*; D051381:Rats; D013234:Stem Cells / Q000378:metabolism
chemical_list: C547077:MIRN132 microRNA, human; D035683:MicroRNAs