title: Microvesicles derived from endothelial progenitor cells enhance neoangiogenesis of human pancreatic islets.
abstract: The efficacy of islet transplantation is limited by poor graft vascularization. We herein demonstrated that microvesicles (MVs) released from endothelial progenitor cells (EPCs) enhanced human islet vascularization. After incorporation into islet endothelium and β-cells, EPC-derived  MVs favored insulin secretion, survival, and revascularization of islets transplanted in SCID mice. MVs induced in vitro islet endothelial cell proliferation, migration, resistance to apoptosis, and organization in vessel-like structures. Moreover, MVs partially overcame the antiangiogenic  effect of rapamycin and inhibited endothelial-leukocyte interaction via L-selectin and CD40. MVs were previously shown to contain defined patterns of mRNAs. Here we demonstrated that MVs carried the proangiogenic miR-126 and miR-296 microRNAs (miRNAs). MVs pretreated with RNase or derived  from Dicer knocked-down EPCs showed a reduced angiogenic effect. In addition, MVs overcame the antiangiogenic effect of the specific antagomiRs of miR-126 and miR-296, suggesting a relevant contribution of miRNAs delivered by MVs to islet endothelium. Microarray analysis of MV-stimulated islet  endothelium indicated the upregulation of mRNAs coding for factors involved in endothelial proliferation, differentiation, and angiogenesis. In addition, MVs induced the activation of the PI3K-Akt and eNOS signaling pathways in islet endothelium. These results suggest that MVs activate an  angiogenic program in islet endothelium that may sustain revascularization and β-cell function.
authors.affiliation: Research Center for Experimental Medicine (CeRMS), University of Torino, Torino, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cantaluppi
authors.forename: Luigi
authors.initials: L
authors.lastname: Biancone
authors.forename: Federico
authors.initials: F
authors.lastname: Figliolini
authors.forename: Silvia
authors.initials: S
authors.lastname: Beltramo
authors.forename: Davide
authors.initials: D
authors.lastname: Medica
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Deregibus
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Renato
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Mauro
authors.initials: M
authors.lastname: Salizzoni
authors.forename: Ciro
authors.initials: C
authors.lastname: Tetta
authors.forename: Giuseppe Paolo
authors.initials: GP
authors.lastname: Segoloni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Camussi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D019013:CD40 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000098:blood supply* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology*; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D019013:CD40 Antigens; D007328:Insulin; C527111:MIRN126 microRNA, human; C549871:MIRN296 microRNA, human; D035683:MicroRNAs; D019041:L-Selectin; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012260:Ribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D020123:Sirolimus