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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.
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