on December 1, 2003
Published online before print December 1, 2003, doi: 10.1161/01.CIR.0000106161.43954.DF
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Submitted on February 27, 2003
From the Institut National de la Santé et de la Recherche Médicale, INSERM U541 (J.S.S., A.G., S.P., B.E., M.D., M.C., B.L., R.M., A.T., Z.M.), INSERM U 343, Hôpital l’Archet, Nice (V.B., H.G.), and Institut des Vaisseaux et du Sang (S.L.R.R., V.B., G.T.), Paris, France. * To whom correspondence should be addressed. E-mail: mallat{at}larib.inserm.fr.
Background--Bone marrow-derived mononuclear cells (BM-MNCs) enhance postischemic neovascularization, and their therapeutic use is currently under clinical investigation. We evaluated the safety of BM-MNC-based therapy in the setting of atherosclerosis. Methods and Results--Apolipoprotein E (apoE)-knockout (KO) mice were divided into 4 groups: 20 nonischemic mice receiving intravenous injection of either saline (n=10) or 106 BM-MNCs from wild-type animals (n=10) and 20 mice with arterial femoral ligature receiving intravenous injection of either saline (n=10) or 106 BM-MNCs from wild-type animals (n=10) at the time of ischemia induction. Animals were monitored for 4 additional weeks. Atherosclerosis was evaluated in the aortic sinus. BM-MNC transplantation improved tissue neovascularization in ischemic hind limbs, as revealed by the 210% increase in angiography score (P<0.0001), the 33% increase in capillary density (P=0.01), and the 65% increase in tissue Doppler perfusion score (P=0.0002). Hindlimb ischemia without BM-MNC transplantation or BM-MNC transplantation without ischemia did not affect atherosclerotic plaque size. However, transplantation of 106 BM-MNCs into apoE-KO mice with hindlimb ischemia induced a significant 48% to 72% increase in lesion size compared with the other 3 groups (P=0.0025), despite similar total cholesterol levels. Transplantation of 105 BM-MNCs produced similar results, whereas transplantation of 106 apoE-KO-derived BM-MNCs had neither proangiogenic nor proatherogenic effects. There was no difference in plaque composition between groups. Conclusions--BM-MNC therapy is unlikely to affect atherosclerotic plaque stability in the short term. However, it may promote further atherosclerotic plaque progression in an ischemic setting.
Revised on September 18, 2003
Accepted on October 16, 2003
Transplantation of Bone Marrow-Derived Mononuclear Cells in Ischemic Apolipoprotein E-Knockout Mice Accelerates Atherosclerosis Without Altering Plaque Composition
Jean-Sébastien Silvestre PhD,
Key words: angiogenesis • inflammation • atherosclerosis
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