Introduction of embryonic stem cells into vein grafts reduces intimal hyperplasia in mice.
OBJECTIVE
Atherosclerosis with its cardiovascular events including cardiac and peripheral ischemia represents the main cause of death in the developed countries. Although interventional treatments like percutaneous transluminal angioplasty or stents are increasingly applied for the treatment of peripheral arterial disease, they are not always technically applicable or durable and bypass surgery is needed. Compared to synthetic grafts, vein grafts show a better patency especially when used for the lower leg as well as a lower risk for infection compared to synthetic grafts. Still the long-term patency rates are unsatisfactory due to accelerated intimal hyperplasia, a thickening of the vessel wall. The aim of this study was to elucidate, if the implantation of embryonic stem cells into vein grafts can reduce the development of intimal hyperplasia in a mouse in vivo model.


METHODS
In this study we implanted LacZ-tagged (ROSA26) murine embryonic stem cells into decellularized vein grafts. Control groups were: 1) untreated veins; 2) decellularized veins; 3) decellularized veins with gel and plastic film; and 4) decellularized veins with smooth muscle cells in gel surrounded by plastic film. Six weeks after insertion into the carotid artery of mice, the grafts were excised and analyzed immunohistochemically, morphologically, and by x-gal staining and compared to the control groups. The Mann-Whitney U test was used to compare groups. Statistical significance was indicated by a value of P<0.05.


RESULTS
Decellularized veins with implanted stem cells showed significantly less intimal thickening compared to all control groups (intimal hyperplasia vs. luminal circumference mean±SD 7.3±3.5 µm, median 8 µm). The control groups: 1) untreated veins (60.3±25.5 µm, median 58.5 µm); 2) decellularized veins (53.9±22.4 µm, median 48.4 µm); 3) decellularized veins with gel and plastic film (70.6±22.4 µm, median 72.6 µm); and 4) decellularized veins with smooth muscle cells in gel surrounded by plastic film (73.5±18.1 µm, median 73.6 µm) all showed the same high degree of intimal hyperplasia.


CONCLUSIONS
This study demonstrates that embryonic stem cells have a therapeutic competence to favourably modulate intimal hyperplasia in vivo.
Department of Vascular and Endovascular Surgery, University Clinic of Cologne, Cologne, Germany - silke.breuer@uk-koeln.de.
S
S
Breuer
P
P
Fogelstrand
H
H
Lindskog
K
K
Osterberg
T
T
Luebke
J
J
Brunkwall
E
E
Mattsson
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D017536:Carotid Artery, Common / Q000473:pathology / Q000601:surgery; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000637:transplantation*; D017930:Genes, Reporter; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D058426:Neointima; D013997:Time Factors; D014162:Transfection; D058017:Vascular Grafting / Q000009:adverse effects / Q000379:methods*; D014682:Vena Cava, Inferior / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D015415:Biomarkers; D001616:beta-Galactosidase