title: Ephrin-B2-activated peripheral blood mononuclear cells from diabetic patients restore diabetes-induced impairment of postischemic neovascularization.
abstract: We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 10(5) PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulating vascular progenitor cells in diabetic nude mice and increased the ability of endogenous bone marrow MNCs to differentiate into cells with endothelial phenotype and enhanced their proangiogenic potential. Therefore, EFNB2 treatment of PB-MNCs abrogates the diabetes-induced stem/progenitor cell dysfunction and opens a new avenue for the clinical development of an innovative and accessible strategy in diabetic patients with critical ischemic diseases.
authors.affiliation: Blood and Vessels Institute, Lariboisière Hospital, Paris, France.
authors.forename: Dong
authors.initials: D
authors.lastname: Broquères-You
authors.forename: Carole
authors.initials: C
authors.lastname: Leré-Déan
authors.forename: Tatiana
authors.initials: T
authors.lastname: Merkulova-Rainon
authors.forename: Chris S
authors.initials: CS
authors.lastname: Mantsounga
authors.forename: David
authors.initials: D
authors.lastname: Allanic
authors.forename: Patricia
authors.initials: P
authors.lastname: Hainaud
authors.forename: Jean-Olivier
authors.initials: JO
authors.lastname: Contrères
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.forename: Marie
authors.initials: M
authors.lastname: Virally
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mourad
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Guillausseau
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D036388:Ephrin-B2 / Q000494:pharmacology*; D006614:Hindlimb / Q000098:blood supply / Q000503:physiopathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology
chemical_list: D036388:Ephrin-B2