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(Circulation. 2006;114:I-167 – I-173.)
© 2006 American Heart Association, Inc.

Cell Transplantation and Tissue Engineering

Collagen Matrices Enhance Survival of Transplanted Cardiomyoblasts and Contribute to Functional Improvement of Ischemic Rat Hearts

Ingo Kutschka, MD; Ian Y. Chen, MSE; Theo Kofidis, MD; Takayasu Arai, MD; Georges von Degenfeld, MD, PhD; Ahmad Y. Sheikh, MD; Stephen L. Hendry, MD; Jeremy Pearl, BS; Grant Hoyt, RA; Ramachadra Sista, MD; Phillip C. Yang, MD; Helen M. Blau, PhD; Sanjiv S. Gambhir, MD, PhD; Robert C. Robbins, MD

From the Department of Cardiothoracic Surgery (I.K., T.K., A.Y.D., S.L.H., J.P., G.H., R.C.R.), Molecular Imaging Program at Stanford, Departments of Radiology and Bioengineering, Bio-X Program (I.Y.C., S.S.G.), Department of Cardiovascular Medicine (T.A., R.S., P.C.Y.), Baxter Laboratory in Genetic Pharmacology, Departments of Molecular Pharmacology and of Microbiology & Immunology (G.v.D., H.M.B.); Stanford University, School of Medicine, Stanford, Calif.

Correspondence to Ingo Kutschka, Department of Thoracic and Cardiovascular Surgery, Klinikum Braunschweig, Salzdahlumerstr. 90, 38126 Germany. E-mail ingo.kutschka{at}t-online.de

Background— Cardiac cell transplantation is limited by poor graft viability. We aimed to enhance the survival of transplanted cardiomyoblasts using growth factor-supplemented collagen matrices.

Methods and Results— H9c2 cardiomyoblasts were lentivirally transduced to express firefly luciferase and green fluorescent protein (GFP). Lewis rats underwent ligation of the left anterior descending artery (LAD) ligation to induce an anterior wall myocardial infarction. Hearts (n=9/group) were harvested and restored ex vivo with 1x10⁶ genetically labeled H9c2 cells either in (1) saline-suspension, or seeded onto (2) collagen-matrix (Gelfoam [GF];), (3) GF/Matrigel (GF/MG), (4) GF/MG/VEGF (10 µg/mL), or (5) GF/MG/FGF (10 µg/mL). Hearts were then abdominally transplanted into syngeneic recipients (working heart model). Controls (n=6/group) underwent infarction followed by GF implantation or saline injection. Cell survival was evaluated using optical bioluminescence on days 1, 5, 8, 14, and 28 postoperatively. At 4 weeks, fractional shortening and ejection fraction were determined using echocardiography and magnetic resonance imaging, respectively. Graft characteristics were assessed by immunohistology. Bioluminescence signals on days 5, 8, and 14 were higher for GF-based grafts compared with plain H9c2 injections (P<0.03). Signals were higher for GF/MG grafts compared with GF alone (P<0.02). GFP-positive, spindle-shaped H9c2 cells were found integrated in the infarct border zones at day 28. Left ventricular (LV) function of hearts implanted with collagen-based grafts was better compared with controls (P<0.05). Vascular endothelial growth factor or fibroblast growth factor did not further improve graft survival or heart function.

Conclusions— Collagen matrices enhance early survival of H9c2 cardiomyoblasts after transplantation into ischemic hearts and lead to improved LV function. Further optimization of the graft design should make restoration of large myocardial infarctions by tissue engineering approaches effective.

Key Words: cells • collagen • imaging • myocardial infarction • transplantation

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