Cell-based gene therapy modifies matrix remodeling after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3–deficient mice Denis.

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Cell-based gene therapy modifies matrix remodeling after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3–deficient mice Denis Angoulvant, MD, PhD, Shafie Fazel, MD, PhD, Richard D. Weisel, MD, Teresa Y.Y. Lai, MSc, Paul W. Fedak, MD, PhD, Liwen Chen, MSc, Shahin Rafati, MD, MSc, Charit K. Seneviratne, PhD, Norbert Degousee, PhD, Ren-Ke Li, MD, PhD The Journal of Thoracic and Cardiovascular Surgery Volume 137, Issue 2, Pages 471-480.e2 (February 2009) DOI: 10.1016/j.jtcvs.2008.08.031 Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 1 In vitro analysis of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) and matrix metalloproteinase-2 (MMP-2). A, Transfection efficiency. β-Galactosidase control vector expression (in blue) 3 days after transfection into bone marrow stromal cells (BMSCs; ×400). B, C, Semiquantitative reverse-transcriptase polymerase chain reaction (B) and densitometry (TIMP-3 mRNA levels normalized relative to glyceraldehyde-3-phosphate dehydrogenase [GAPDH] expression: TIMP-3/GAPDH). (C), Analyses showing TIMP-3 mRNA levels and GAPDH expression at days (D) 1, 2, 3, and 6 after cultured BMSCs were transfected with timp-3 (BMSC-T3) or vector (BMSC). Bsl, baseline; C1, control sample without reverse transcription; T3, TIMP-3 plasmid; C2, solution control; n = 5 gels in (C). ∗P < .05 compared with Bsl. D, E, Time course analysis of TIMP-3 protein levels by immunoblot in cell lysis and supernatant at Bsl and days (D) 3, 6, and 10 after timp-3 transfection. Bsl, Nontransfected cells (cell lysis) or culture medium (supernatant); MW, molecular weight; n = 6 gels in E. ∗∗P < .01 compared with Bsl; #P < .001 compared with Bsl. F–H, Gelatin zymography (F) with immunoblot (G) and densitometry analysis (H), showing a significant reduction (∼30%; P < .01) in MMP-2 activity in the supernatant, with no difference in MMP-2 expression in the cell lysis or supernatant or in internal standard GAPDH expression, 3 days after transfection in the BMSC-T3 group relative to the BMSC group. PC, Positive control; n = 6 samples per group in H, equal amounts of protein loaded. Data are mean ± standard error of the mean. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 471-480.e2DOI: (10.1016/j.jtcvs.2008.08.031) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 2 In vivo analysis of matrix metalloproteinase (MMP) activity and apoptosis. A, B, Densitometry analyses estimating MMP activity in myocardial extracts at days 3, 7, and 28 after implantation of culture medium, bone marrow stromal cells (BMSCs), or timp-3-transfected BMSCs (BMSC-T3). The pooled results demonstrate that MMP-9 (A) and MMP-2 (B) gelatinolytic activities were reduced at day 3 after implantation of BMSC-T3 (n = 6 per group per time point). Gelatin zymography does not measure what activity is inactivated by natural inhibitors in vivo. C–F, Representative light micrographs (×400) illustrating terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining of apoptotic cells (arrows) in the border zone of mouse hearts 3 days after implantation of medium (C), BMSCs (D), or BMSC-T3 (E). Normal myocardium (No MI, F) is presented as a positive control. Scale bar = 50 μm in (C–F). G, Apoptotic nuclei (expressed as a % of total cells per field on days [D] 3, 7, and 28 after implantation; n = 5 per group per time point) were significantly reduced at D3 with BMSC implantation, and further reduced with BMSC-T3 implantation. The depression in apoptotic cell numbers persisted at D7 in the BMSC-T3 compared with the medium group. No significant differences were observed between groups at D28. Data are mean ± standard error of the mean. ∗P < .05 versus medium, ∗∗P < .01 versus medium; #P < .05 versus BMSCs; ‡P < .01 versus BMSCs. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 471-480.e2DOI: (10.1016/j.jtcvs.2008.08.031) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 3 Collagen content and structure in the remote myocardium. A–D, Representative confocal micrographs (left ventricular sections) showing the fibrillar collagen network (stained with picrosirius red, arrows) in normal myocardium (No MI, A), and in the remote (noninfarcted) myocardium of infarcted animals, 28 days after implantation of medium (B), bone marrow stromal cells (BMSC, C) or timp-3-transfected BMSCs (BMSC-T3, D). Cardiomyocytes appear green due to autofluorescence. Scale bar = 50 μm in (A–D). Collagen fibers and connectivity were clearly preserved in the BMSC group and further preserved in the BMSC-T3 group. E–G, Collagen content (expressed as % of pixel2, E), fibril length (F), and fibril diameter (G), determined for all 4 groups (n = 6 per group for Medium, BMSC, BMSC-T3; n = 4 for No MI) by computer image analysis of confocal stacks, were all increased to No MI levels by BMSC-T3 implantation. Data are mean ± standard error of the mean. ∗P < 0.05 versus medium, #P < .05 versus BMSC, †P < .05 versus No MI. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 471-480.e2DOI: (10.1016/j.jtcvs.2008.08.031) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 4 Capillary density. A–G, Representative light micrographs (×250) showing CD31 staining (vascular structure; brown in color) in the infarct border zone (A–F) of hearts at days (D) 3 and 7 after implantation of medium (A, D), bone marrow stromal cells (BMSC, B, E) or timp-3-transfected BMSCs (BMSC-T3, C, F). Normal myocardium (No MI, G) was a positive control. Scale bar = 25 μm in A–G. H, Blood vessel density (expressed as number of capillaries per mm2; n = 5 per group per time point) was significantly greater at D3 with BMSC implantation compared with BMSC-T3. By D7, vessel density was equally increased in both cell transplant groups. Data are mean ± standard error of the mean. ∗P < .05 versus medium, #P < .05 versus BMSC. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 471-480.e2DOI: (10.1016/j.jtcvs.2008.08.031) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions

Figure 5 Left ventricular (LV) morphometry and function. A, Representative macrographs of heart slices at 28 days after myocardial infarction (MI) and implantation of medium, bone marrow stromal cells (BMSC), or timp-3-transfected-BMSCs (BMSC-T3). Increased infarct size and LV dilatation is apparent in medium control hearts compared with those from BMSC and BMSC-T3 groups. B, These observations are confirmed by echocardiographic parasternal small-axis M mode images of the hearts for morphologic study. C, By echocardiography (n = 6 per group per time point), LV dilatation (body weight-indexed LV end diastolic dimension in mm/g) over 28 days following MI was significantly reduced (relative to medium controls) after implantation of BMSC (at days 7 and 28; P < .05) and BMSC-T3 (at days 3, 7, 28; P < .01). D, LV systolic function (fractional area change in %) over 28 days following MI was significantly preserved after implantation of BMSC (compared with medium controls) and BMSC-T3 (compared with BMSC and medium groups). E, F, By morphometric assessment (n = 6 per group), LV infarcted areas (expressed as % of LV surface, E), and body weight–indexed LV chamber volumes (normal heart [No MI, n = 3] as control, F) were significantly smaller (compared with medium controls) at 28 days (D) after BMSC or BMSC-T3 implantation. No significant differences were observed between BMSC and BMSC-T3 groups. Data are mean ± standard error of the mean. ∗P < .05 versus medium. The Journal of Thoracic and Cardiovascular Surgery 2009 137, 471-480.e2DOI: (10.1016/j.jtcvs.2008.08.031) Copyright © 2009 The American Association for Thoracic Surgery Terms and Conditions