Percutaneous transplantation of genetically-modified autologous fibroblasts in the rabbit femoral artery: a novel approach for cardiovascular gene therapy

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Percutaneous transplantation of genetically-modified autologous fibroblasts in the rabbit femoral artery: a novel approach for cardiovascular gene therapy Mikael Mazighi, MD, Didier Tchétché, MD, Yann Gouëffic, MD, Aurélie San Juan, BSc, Liliane Louedec, MS, Dominique Hénin, MD, Jean-Baptiste Michel, MD, PhD, Marie-Paule Jacob, PhD, Laurent J. Feldman, MD, PhD Journal of Vascular Surgery Volume 44, Issue 5, Pages 1067-1075.e1 (November 2006) DOI: 10.1016/j.jvs.2006.07.022 Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 1 Digital angiogram of the rabbit iliofemoral arteries before percutaneous local delivery of autologous fibroblasts. Note that care was taken to select a target arterial segment (between black arrowheads) without angiographically visible side branches to limit fibroblast loss during local delivery. Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 2 The Dispatch catheter used for cell transplantation incorporates a 20-mm-long × 3-mm-diameter spiral inflation coil wrapped around an urethane sheath covered by a layer of 24 perforated channels, each with a single 100-μm infusion opening through which cells are delivered via an independent infusion lumen. Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 3 Transfection of autologous rabbit skin fibroblasts in vitro. A-B, Time-course of human tissue inhibitor of metalloproteinase 1 (hTIMP-1) and nls-LacZ protein secretion after FuGene-mediated transfection. A, The hTIMP-1 concentration in the conditioned medium. B, The percentage of nls-LacZ-positive fibroblasts peaked 3 days after transfection, then decreased but remained detectable up to 21 days. Black diamonds, white triangles, and black squares indicate hTIMP-1-transfected, nls-LacZ-transfected, and non-transfected fibroblasts, respectively. *P < .05 vs days 0. Results represent the means of five experiments and are expressed as means ± SD. C, Representative example of nls-LacZ-transfected cultured fibroblasts. Blue nuclei indicate nls-LacZ gene expression (X-gal staining) (magnification ×500). D, Nontransfected cultured fibroblasts (magnification ×500). Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 4 In vivo percutaneous transplantation of autologous fibroblasts in the balloon-injured rabbit femoral artery. A, Fluorescence microscopy detected fluorescent fibroblasts (white arrowheads) along the luminal border of the target arterial segment 1 hour after local cell delivery with the Dispatch catheter. B, Note the absence of fluorescence in the control femoral artery incubated with Dulbecco Modified Eagle’s Medium (DMEM) alone (original magnification ×20 magnification). C, Scanning electron microscopy shows foci of round fibroblasts (Fibro) entrapped in a mesh of fibrin (F), and red blood cells (RBC) are visible at the surface of the femoral artery incubated with autologous fibroblasts, D, but not in the control artery incubated with DMEM alone. Note that the absence of engrafted fibroblasts in the control artery unmasks the presence of abundant platelets (P) at the balloon-injured site. Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig 5 In vivo percutaneous transplantation of genetically modified autologous fibroblasts in the stented rabbit femoral artery. A, Time course of ex vivo human tissue inhibitor of metalloproteinase 1 (hTIMP-1) protein secretion in stented arteries incubated in vivo with hTIMP-1-transfected (black diamonds), nls-LacZ-transfected (white triangles), or nontransfected (black squares) fibroblasts, or with DMEM alone (white squares). The hTIMP-1 concentration in the conditioned medium of arteries incubated with hTIMP-1-transfected fibroblasts peaked 3 days after fibroblast transplantation, then decreased by 90% at 14 days and was undetectable at 28 days. It was not detected in the three other groups. Results were normalized to the tissue wet weight and represent the means of 12 arteries in each group. Data are expressed as means ± SD. *P < .05 vs days 0. B-C, Representative examples of nls-LacZ-positive fibroblasts engrafted at the surface of stented femoral arteries. Arteries were examined en face before (B; original magnification ×40 magnification) and after (C; original magnification ×10) removal of stent struts. Note the presence of clusters of nls-LacZ-positive fibroblasts (black arrowheads) at the arterial surface. Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig e1 (online only) En face view of hematoxylin-stained femoral arteries engrafted with Dulbecco Modified Eagle’s Medium (DMEM) (A) or fibroblasts (B). Note the presence of foci of hematoxylin-stained nuclei (black arrowheads) over the luminal aspect of the artery only after fibroblast delivery (B). The absence of such pattern in arteries incubated with DMEM alone (A) suggests that cells present at the surface of the artery incubated with fibroblasts are engrafted fibroblasts (original magnification ×20). Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig e2 (online only) Bar graph shows lactate dehydrogenase (LDH) dosage (expressed in optical density units) in the conditioned culture media of rabbit femoral arteries incubated with Dulbecco Modified Eagle’s Medium (DMEM) (black bars), nontransfected fibroblasts (hatched bars), nls-LacZ-transfected fibroblasts (grey bars) or hTIMP-1–transfected fibroblasts (white bars) (n = 6 in each group). Data are expressed as mean ± SD. Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions

Fig e3 (online only) Scatter graph shows the relationship between human tissue inhibitor of metalloproteinase 1 (hTIMP-1) concentration and intimal growth. No correlation between hTIMP-1 and intima/media ratio was observed (n = 6). Journal of Vascular Surgery 2006 44, 1067-1075.e1DOI: (10.1016/j.jvs.2006.07.022) Copyright © 2006 The Society for Vascular Surgery Terms and Conditions