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Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice  Ryotaro Hashizume, MD, Aika Yamawaki-Ogata,

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Presentation on theme: "Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice  Ryotaro Hashizume, MD, Aika Yamawaki-Ogata,"— Presentation transcript:

1 Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice  Ryotaro Hashizume, MD, Aika Yamawaki-Ogata, MS, Yuichi Ueda, MD, PhD, William R. Wagner, PhD, Yuji Narita, MD, PhD  Journal of Vascular Surgery  Volume 54, Issue 6, Pages (December 2011) DOI: /j.jvs Copyright © 2011 Society for Vascular Surgery Terms and Conditions

2 Fig 1 Gene expression from macrophages and smooth muscle cells (SMCs) cocultured with mesenchymal stem cells (MSCs). A, Gene expression of matrix metalloproteinase (MMP)-2, MMP-9, and tumor necrosis factor-α (TNF-α) from macrophage decreased with MSC coculture (n = 5-6 per group). B, and C, Gene expression of MMPs from SMCs was not changed in time. D, Elastin expression at 48 and 96 hours was significantly increased (n = 5-9 per group). *P < .05 compared with monoculture group. Data are mean ± standard deviation (error bar). GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Aortic tissue culture ex vivo with or without mesenchymal stem cells (MSCs). A, Under light microscopy, elastica van Giesen staining revealed focal destruction of the medial elastin network in monoculture group at 14 days of incubation. In contrast, aorta cocultured with MSCs exhibited improved preservation of the medial elastin architecture. Scale bars = 50 μm. B, A quantitative analysis of elastic lamellae, elastin content, and gap area of the aortic media showed no significant differences between the groups in the number of elastic lamellae but significantly lower elastin content and higher gap area in the monoculture compared with the coculture with MSCs (n = 5, respectively). *P < .01 compared with monoculture group. C, Elastin content of the cocultured aorta was fairly well preserved, whereas for the monocultured aorta, it decreased with time (n = 5, respectively). *P < .05 compared with monoculture group at same time point. Data are mean ± standard deviation (error bar). D, Representative bands of gel zymography for pro-matrix metalloproteinase (MMP)-2 and active MMP-2 are shown. E, Gelatinolytic activity of pro-MMP-2 significantly decreased in the coculture group from 3 through 14 days of incubation, likewise active MMP-2 in the coculture group correspondingly decreased at 7 and 14 days (n = 5, respectively). *P < .05 compared with monoculture group at same time point. Data are mean ± standard deviation (error bars). Aortic tissue monoculture control data (without MSCs) in C and E, are from Yamawaki-Ogata A et al.15 Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Mesenchymal stem cell (MSC) implantation attenuates aneurysmal growth in vivo. A, Representative macroscopic images of apolipoprotein E-deficient (apoE−/−), apoE−/− + angiotensin II (Ang II), and apoE−/− + Ang II + MSC aortas. The arrowheads indicate typical aneurysm formation in apoE−/− + Ang II mice. Scale bar = 10 mm. Aortic outer diameter was measured in all groups at three different positions: (B) ascending, (C) phrenic, and (D) infrarenal. At the ascending aorta and phrenic level, Ang II-infused mice with (n = 7) or without (n = 6) MSC implantation had significantly increased aortic diameters compared with apoE−/− mice (n = 6), whereas at the level of infrarenal aorta, the diameter of the apoE−/− + Ang II + MSC mice was significantly lower than that of the apoE−/− + Ang II mice. Data are mean ± standard deviation. †P < .05 vs apoE−/− group. Data for groups without MSCs are from Yamawaki-Ogata A et al.15 *P < .05 vs apoE−/− + Ang II group. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

5 Fig 4 Mesenchymal stem cells (MSCs) inhibit elastin degradation in the aortic wall of apolipoprotein E-deficient (apoE−/−) + angiotensin II (Ang II) infusion model as well as aortic dilation. A, D, Elastica van Giesen staining images of apoE−/−, (B and E) apoE−/− + Ang II, and (C and F) apoE−/− + Ang II + MSC, show extensive fracturing of the elastic lamellae in apoE−/− + Ang II aorta (arrows). Scale bars = 200 μm. G, Elastin measurement shows preserved elastin content in apoE−/− + Ang II + MSC aorta (n = 6-7, respectively). †P < .05 vs apoE−/− group. *P < .05 vs apoE−/− + Ang II group. Data are mean ± standard deviation. H, Elastin content and aortic diameter at the infrarenal level show an inverse distribution pattern (n = 12 in total). Data for groups without MSCs in (G) and (H) are from Yamawaki-Ogata A et al.15 Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

6 Fig 5 Matrix metalloproteinases (MMPs) were downregulated and insulin-like growth factor-1 (IGF-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) were upregulated by mesenchymal stem cell (MSC) implantation in vivo. A, Representative bands of gel zymography for MMPs of apolipoprotein E-deficient (apoE−/−) (n = 6), apoE−/− + angiotensin II (Ang II) (n = 6), and apoE−/− + Ang II + MSC (n = 7) aortas. B and C, MMPs (0.02 units) were loaded as a positive control. Activities in (B) MMP-2 and (C) MMP-9 were significantly decreased in apoE−/− + Ang II + MSC aorta compared with apoE−/− + Ang II aorta. *P < .05 vs apoE−/− + Ang II group. Data are mean ± standard deviation. Significant positive correlations were shown between (D) elastin and IGF-1 content, and between (E) elastin and TIMP-1 (n = 13 in total, respectively) among Ang II infusion groups. B-E, Data for groups without MSCs are from Yamawaki-Ogata A et al.15 Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

7 Fig 6 Mesenchymal stem cells (MSCs) suppressed macrophage aggregation in the aortic wall, and wall elastin content is inversely associated with matrix metalloproteinase (MMP) presence and activity in vivo. A and D, Representative hematoxylin and eosin staining, and B and E (original magnification ×200) immunostaining for F4/80 in serial aortic sections without or with MSC implantation, respectively. Nuclear staining is blue and anti-F4/80 for macrophage labeling is green (yellow arrowheads). The black boxes indicate higher magnification areas shown in B and E, respectively. C and F, Immunostaining with secondary antibody without primary antibody was used as a negative control. G-L, Cell tracking and characterization of implanted MSCs. G and H, Cell tracking by PKH labeling (red, white arrowheads) showed implanted MSCs remain adjacent to the aorta 28 days after implantation. Implanted PKH26-labeled MSCs explanted after 28 days exhibited positive labeling for (I and J) Sca-1 and (K and L) CD106, both of which were also positive before implantation. The insets in I and K, show PKH26-positive area. J and L, High-magnification views in insets show MSCs coexpressed the targeted antigens (original magnification ×400). All aortic sections were from the suprarenal aorta. Scale bars = 100 μm. M, Significant negative correlations were shown between elastin content in the aortic wall and all MMPs tested by gelatin zymography in the in vivo study (n = in total, respectively). Summary data for groups without MSCs in (M) appear in Yamawaki-Ogata A et al.15 Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

8 Supplemental Figure 1 Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

9 Supplemental Figure 2 Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

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