Proinflammatory role of stem cells in abdominal aortic aneurysms

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Proinflammatory role of stem cells in abdominal aortic aneurysms Evan J. Ryer, MD, Robert P. Garvin, MD, Charles M. Schworer, PhD, Kamell R. Bernard-Eckroth, MD, Gerard Tromp, PhD, David P. Franklin, MD, James R. Elmore, MD, Helena Kuivaniemi, MD, PhD Journal of Vascular Surgery Volume 62, Issue 5, Pages 1303-1311.e4 (November 2015) DOI: 10.1016/j.jvs.2014.04.067 Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 1 Cells positive for c-kit in the media and adventitia layers of two 78-year-old men, one with a normal diameter aorta (control) and one with an 8-cm abdominal aortic aneurysm (AAA). Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 2 Cells positive for cluster of differentiation (CD) 34 in the media and adventitia layers of a 59-year-old woman with a normally sized aorta (control) and 63-year-old woman with a 5.1-cm abdominal aortic aneurysm (AAA). Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 3 Cells positive for Stro1 in the media and adventitia layers of a 53-year-old man with a normally sized aorta (control) and 55-year-old man with a 5.5-cm abdominal aortic aneurysm (AAA). Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 4 Quantification of immunostaining for c-kit, CD34, and Stro1 in the media and adventitia layers of aortic tissue samples from abdominal aortic aneurysms (AAAs) and nonaneurysmal aorta (controls). The results in percentages of positively stained cells are presented as box-and whisker-plots showing the median (center line of box) and interquartile range (IQR; box edges), and at 1.5× the IQR (whiskers), with the open circles indicating outliers beyond the 1.5× IQR. P values were obtained by using Wilcoxon rank sum test (Mann-Whitney U). Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 5 Double immunofluorescence staining with (A) the smooth muscle cell marker SM22, (B) the macrophage marker CD68, and the (A and B) stem cell marker c-kit in a 78-year-old man with an 8-cm abdominal aortic aneurysm (AAA). Merged imaging includes 4′,6-diamidino-2-phenylindole staining of nuclei. Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 6 Double immunofluorescence staining with (A) the fibroblast marker FSP1, (B) the macrophage marker CD68, and (A and B) the stem cell marker CD34 in a 61-year-old woman with a 5.1-cm abdominal aortic aneurysm (AAA). Merged imaging includes 4′,6-diamidino-2-phenylindole staining of nuclei. Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Fig 7 Double immunofluorescence staining with (A) the macrophage marker CD68, (B) the smooth muscle cell marker SM22, (C) the fibroblast marker FSP1, and (A, B, and C) the stem cell marker c-kit in a 70-year-old man who underwent open abdominal aortic aneurysm (AAA) repair. Merged imaging includes 4′,6-diamidino-2-phenylindole staining of nuclei. Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Supplementary Fig 1 (online only) Double-immunofluorescence staining with the cell proliferation marker Ki-67 and the macrophage marker CD68 in (A) a 78-year-old man with an 8-cm abdominal aortic aneurysm (AAA) and (B) 70-year-old man with a 5.5-cm AAA. Merged imaging includes 4′,6-diamidino-2-phenylindole staining of nuclei. Original magnification ×400. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Supplementary Fig 2 (online only) Messenger RNA (mRNA) expression of genes involved in macrophage activation and transforming growth factor-β-induced differentiation of stem cells into vascular smooth muscle cells. Box-and-whisker plots of mRNA levels for the genes that had significantly (false discovery rate <0.05) different expression levels between specimens of abdominal aortic aneurysm (AAA) patients (red boxes; n = 6) and controls (light blue boxes; n = 7) matched for age, sex, and ethnicity obtained from the abdominal aorta. Results are based on our microarray expression profiling, which have been described previously.3 RNA expression levels in signal intensity units are indicated on the ordinate axis. The horizontal bars in the boxes indicate median values, the box edges indicate the interquartile range, the whiskers indicate range of nonoutlier values, and circles indicate outliers of <3 interquartile range units. Gene symbols available from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/) were used. Supplementary Table II (online only) provides additional information. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions

Supplementary Fig 3 (online only) A network of the interactions of selected differentially expressed genes. The Ingenuity Pathway Analysis tool (Qiagen, Valencia, Calif) was used to perform a network analysis for a set of differentially expressed genes (Supplementary Table II, online only). The Fig shows the network with a score of 32 and 13 of the differentially expressed genes. Molecules with increased expression (red) and those with decreased expression (green) were identified in our previous microarray study comparing the messenger RNA (mRNA) levels between abdominal aortic aneurysm (AAA) group and samples of infrarenal aorta from age and sex-matched controls.3 Solid lines represent direct interactions and dashed lines indirect interactions. Journal of Vascular Surgery 2015 62, 1303-1311.e4DOI: (10.1016/j.jvs.2014.04.067) Copyright © 2015 Society for Vascular Surgery Terms and Conditions