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Publications de l’équipe Exosomes et croissance tumorale Année de publication : 2005 Jean-Sébastien Silvestre, Clotilde Théry, Bernard Lévy, Alain Tedgui, Sebastian Amigorena, Ziad Mallat (2005 Aug 24) [Lactadherin promotes VEGF-dependent neovascularization]. Mé decine sciences : M/S : 683-5 Résumé Elodie Segura, Sebastian Amigorena, Clotilde Théry (2005 Jul 2) Mature dendritic cells secrete exosomes with strong ability to induce antigenspecific effector immune responses. Blood cells, molecules & diseases : 89-93 Résumé Exosomes are secreted vesicles formed in late endocytic compartments. Immature dendritic cells (DCs) secrete exosomes which transfer functional MHC-peptide complexes to other DCs. Since immature and mature DCs induce different functional T cell responses (i.e., tolerance versus priming), we asked whether DC maturation also influenced the priming abilities of their exosomes. We show that immature and mature murine DCs secrete morphologically similar exosomes. Extensive proteomic analysis of the two exosome populations showed identical overall protein composition, and provided an exhaustive image of the protein composition of DC-derived exosomes. By quantitative analysis, however, exosomes from mature DCs proved enriched in MHC class II, B7.2, ICAM-1, and depleted in MFG-E8, as compared to immature exosomes. In functional T cell stimulation assays, exosomes secreted by mature DCs were 50- to 100-fold more potent than exosomes from immature DCs, both in vitro and in vivo. MHC class II and ICAM-1 were necessary for the increased immune activity of exosomes secreted by mature DCs. Therefore, changes in protein composition and priming abilities of exosomes reflect the maturation signals received by DCs. Philippe Véron, Elodie Segura, Gaël Sugano, Sebastian Amigorena, Clotilde Théry (2005 Jun 29) Accumulation of MFG-E8/lactadherin on exosomes from immature dendritic cells. Blood cells, molecules & diseases : 81-8 Résumé Exosomes are vesicles of endocytic origin secreted spontaneously by dendritic cells (DCs). We have shown previously that exosomes can transfer antigen or MHC-peptide complexes between DCs, thus potentially amplifying the immune response. We had also identified milk fat globule EGF/factor VIII (MFG-E8), also called lactadherin, as one of the major exosomal proteins. MFG-E8 has two domains: an Arg-Gly-Asp sequence that binds integrins alphavbeta3 and alphavbeta5 (expressed by human DCs and macrophages) and a INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1 Publications de l’équipe Exosomes et croissance tumorale phosphatidyl-serine (PS) binding sequence through which it associates to PS-containing membranes (among which exosomes). MFG-E8 is thus a good candidate molecule to address exosomes to DCs. Here, we show that MFG-E8 is expressed by immature bone-marrowderived DCs (BMDCs) and secreted in association with exosomes in vitro. We have generated mice expressing an inactive form of MFG-E8, fused to beta-galactosidase. Analyzing these mice, we demonstrate that MFG-E8 is expressed in vivo in splenic DCs. In a mouse DCdependent, antigen-specific, CD4 T cell-stimulation assay, exosomes produced by MFG-E8deficient BMDCs were barely less efficient than exosomes bearing MFG-E8. We conclude that MFG-E8 is efficiently targeted to exosomes but is not essential to address exosomes to mouse BMDCs. Involvement of MFG-E8/lactadherin in exosome targeting to other DC subpopulations, or to human DCs, is still possible. Jean-Sébastien Silvestre, Clotilde Théry, Ghislaine Hamard, Jacques Boddaert, Barbara Aguilar, Alain Delcayre, Christophe Houbron, Radia Tamarat, Olivier Blanc-Brude, Sylvia Heeneman, Michel Clergue, Micheline Duriez, Régine Merval, Bernard Lévy, Alain Tedgui, Sebastian Amigorena, Ziad Mallat (2005 Apr 19) Lactadherin promotes VEGF-dependent neovascularization. Nature medicine : 499-506 Résumé Vascular endothelial growth factor (VEGF)-induced blood vessel growth is involved in both physiological and pathological angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGF-dependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with alphavbeta3 and alphavbeta5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced alphavbeta3and alphavbeta5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGF-dependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization. INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2