Ephrin-B2–Activated Peripheral Blood Mononuclear Cells From Diabetic Patients Restore Diabetes-Induced Impairment of Postischemic Neovascularization

Author:

Broquères-You Dong12,Leré-Déan Carole13,Merkulova-Rainon Tatiana13,Mantsounga Chris S.13,Allanic David13,Hainaud Patricia13,Contrères Jean-Olivier13,Wang Yu2,Vilar José2,Virally Marie4,Mourad Jean-Jacques5,Guillausseau Pierre-Jean4,Silvestre Jean-Sébastien2,Lévy Bernard I.123

Affiliation:

1. Blood and Vessels Institute, Lariboisière Hospital, Paris, France

2. INSERM U970, Paris Cardiovascular Research Center, Paris, France

3. INSERM U965, Lariboisière Hospital, Paris, France

4. Assistance Publique Hopitaux de Paris, Department of Internal Medicine B, Lariboisière Hospital, Paris, France

5. Assistance Publique Hopitaux de Paris, Department of Internal Medicine and Arterial Hypertension, Avicenne Hospital, Bobigny, France

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, 105 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.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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