title: 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.
  
  
  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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, 41, Bd de la Chapelle, 75010 Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.forename: Andrea
authors.initials: A
authors.lastname: Gojova
authors.forename: Valérie
authors.initials: V
authors.lastname: Brun
authors.forename: Stéphane
authors.initials: S
authors.lastname: Potteaux
authors.forename: Bruno
authors.initials: B
authors.lastname: Esposito
authors.forename: Micheline
authors.initials: M
authors.lastname: Duriez
authors.forename: Michel
authors.initials: M
authors.lastname: Clergue
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Ricousse-Roussanne
authors.forename: Véronique
authors.initials: V
authors.lastname: Barateau
authors.forename: Régine
authors.initials: R
authors.lastname: Merval
authors.forename: Hervé
authors.initials: H
authors.lastname: Groux
authors.forename: Gérard
authors.initials: G
authors.lastname: Tobelem
authors.forename: Bernard
authors.initials: B
authors.lastname: Levy
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000628:therapy*; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D018932:Chemokine CCL2 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D018450:Disease Progression; D005263:Femoral Artery; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000628:therapy*; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D012449:Safety; D012850:Sinus of Valsalva / Q000473:pathology*; D017211:Treatment Failure; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D018932:Chemokine CCL2; D042461:Vascular Endothelial Growth Factor A; D002784:Cholesterol