Transplantation of Bone Marrow–Derived Mononuclear Cells in Ischemic Apolipoprotein E–Knockout Mice Accelerates Atherosclerosis Without Altering Plaque Composition

Abstract

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 10 6 BM-MNCs from wild-type animals (n=10) and 20 mice with arterial femoral ligature receiving intravenous injection of either saline (n=10) or 10 6 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 10 6 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 10 5 BM-MNCs produced similar results, whereas transplantation of 10 6 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.