Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model

• Published in: European journal of cardio-thoracic surgery 2014-05, Vol.45 (5), p.e156-e165
• Main Authors: Yamawaki-Ogata, Aika, Fu, Xianming, Hashizume, Ryotaro, Fujimoto, Kazuro L., Araki, Yoshimori, Oshima, Hideki, Narita, Yuji, Usui, Akihiko
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Animals; Aorta - metabolism; Aorta - pathology; Aortic Aneurysm - pathology; Aortic Aneurysm - therapy; Bone Marrow Transplantation; Disease Models, Animal; Elastin - analysis; Elastin - metabolism; Male; Matrix Metalloproteinase 2 - analysis; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - analysis; Matrix Metalloproteinase 9 - metabolism; Mesenchymal Stem Cell Transplantation; Mice; Mice, Transgenic
• ISSN: 1010-7940; 1873-734X
• DOI: 10.1093/ejcts/ezu018

OBJECTIVES 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 × 106 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.