title: Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model.
abstract: OBJECTIVE
  An aortic aneurysm (AA) is caused by atherosclerosis with chronic inflammation. Mesenchymal stem cells (MSCs) have potential anti-inflammatory properties. In this study, we examined whether an already-formed AA can be treated by intravenous injection of bone marrow-derived (BM)-MSCs in a mouse model.
  
  
  METHODS
  AA was induced in apolipoprotein E-deficient mice by angiotensin II-infusion for 28 days through sub-cutaneous osmotic mini-pumps. After that, 1 × 10(6) BM-MSCs (in 0.2 ml saline) or 0.2 ml saline as a control was injected via the tail vein. Mice were sacrificed at 2 (saline group n = 10, BM-MSC group n = 10), 4 (saline group n = 6, BM-MSC group n = 7) or 8 weeks (saline group n = 5, BM-MSC group n = 6) after injection. The aortic tissues of each group were dissected. Aortic diameter, elastin content, matrix metalloproteinase (MMP)-2 and -9 enzymatic activity and cytokine concentrations were measured, as was macrophage infiltration, which was also evaluated histologically.
  
  
  RESULTS
  The incidence of AA in the BM-MSC group was reduced at 2 weeks (BM-MSC 40% vs saline 100%, P < 0.05), and aortic diameter was reduced at 2 and 4 weeks (2 weeks: 1.40 vs 2.29 mm, P < 0.001; 4 weeks: 1.73 vs 2.32 mm, P < 0.05). The enzymatic activities of MMP-2 and -9 were reduced in the BM-MSC group at 2 weeks (active-MMP-2: 0.28 vs 0.45 unit/ml, P < 0.05; active-MMP-9: 0.16 vs 0.34 unit/ml, P < 0.05). Inflammatory cytokines were down-regulated in the BM-MSC group (interleukin-6: 2 weeks: 1475.6 vs 3399.5 pg/ml, P < 0.05; 4 weeks: 2184.7 vs 3712.8 pg/ml, P < 0.05 and monocyte chemotactic protein-1: 2 weeks: 208.0 vs 352.7 pg/ml, P < 0.05) and insulin-like growth factor (IGF)-1 and tissue inhibitor of metalloproteinase (TIMP)-2 were up-regulated in the BM-MSC group at 2 weeks (IGF-1: 4.7 vs 2.0 ng/ml, P < 0.05; TIMP-2: 9.5 vs 4.0 ng/ml, P < 0.001). BM-MSC injection inhibited infiltration of M1 macrophages and preserved the construction of elastin.
  
  
  CONCLUSIONS
  Our results suggest that BM-MSCs might be an effective treatment for AA. Further investigation is necessary to optimize the injected dosage and the frequency of BM-MSCs to prevent a transient effect.
authors.affiliation: Department of Cardiac Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Yamawaki-Ogata
authors.forename: Xianming
authors.initials: X
authors.lastname: Fu
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Hashizume
authors.forename: Kazuro L
authors.initials: KL
authors.lastname: Fujimoto
authors.forename: Yoshimori
authors.initials: Y
authors.lastname: Araki
authors.forename: Hideki
authors.initials: H
authors.lastname: Oshima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Narita
authors.forename: Akihiko
authors.initials: A
authors.lastname: Usui
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001014:Aortic Aneurysm / Q000473:pathology / Q000628:therapy*; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D004549:Elastin / Q000032:analysis / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D004549:Elastin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Aortic aneurysm; Bone marrow-derived mesenchymal stem cells; Elastin; Intravenous injection; Macrophage; Matrix metalloproteinases