Combined transplantation of skeletal myoblasts and bone marrow stem cells for myocardial repair in rats

Objectives: To prove whether intramyocardial transplantation of combined skeletal myoblasts (SM) and mononuclear bone marrow stem cells is superior to the isolated transplantation of these cell types after myocardial infarction in rats. Methods: In 67 male Fischer rats myocardial infarction was induced by direct ligature of the LAD. Seven days postinfarction baseline echocardiography and intramyocardial cell transplantation were performed. Via lateral thoracotomy 200 mul containing either 10(7) SMs or 10(7) bone marrow-derived mononuclear cells (BM-MNC) or a combination of 5 x 10(6) of both cell types (MB) were injected in 10-15 sites in and around the infarct zone. In controls (C) 200 mul of cell-free medium were injected in the same manner. Before injection both cell types were stained using a fluorescent cell linker kit (PKH, Sigma). In addition, SMs were transfected with green fluorescent protein. Nine weeks postinfarction follow-up echocardiography was performed and animals were sacrificed for further analysis. Results: At baseline echocardiography there was no difference in left ventricular ejection fraction (LVEF; C, SM, BM-MNC, MB: 60.1 +/- 3.2, 53.3 +/- 10.2, 53.1 +/- 8.7, 49 +/- 9.0%) and left ventricular end diastolic diameter (LVEDD; C, SM, BM-MNC, MB: 6.5 +/- 0.8, 5.17 +/- 0.8, 5.77 +/- 1.4, 6.25 +/- 0.8 mm) between the different therapeutic groups. Eight weeks after cell transplantation LVEDD was significantly increased in all animals except those that received a combination of myoblasts and bone marrow stem cells (MB; C, SM, BM-MNC, MB: 7.7 +/- 0.6 mm, P = 0.00 1; 7.7 +/- 1.5 mm, P < 0.001; 7.7 +/- 1.1 mm, P = 0.005; 6.6 +/- 1.7 mm, P = 0.397). At the same time LVEF decreased significantly in the control group (C), stayed unchanged in animals that received bone marrow stem cells (BM-MNC) and increased in animals that received myoblasts (SM) and a combination of both cell types (NIB; C, SM, BM-MNC, MB: 45.3 +/- 7.0%, P = 0.05; 63.9 +/- 15.4%, P = 0.044; 54.3 +/- 6.3%, P = 0.607; 63.0 +/- 11.5%, P = 0.039). Conclusions: The present data show that the concept of combining SMs with bone marrow-derived stem cells may be of clinical relevance by merging the beneficial effects of each cell line and potentially reducing the required cell quantity. Further studies are required to identify the exact mechanisms underlying this synergy and to allow full exploitation of its therapeutic potential. (C) 2004 Elsevier B.V. All rights reserved.