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Dose-Dependent Relationship of Bone Marrow Mesenchymal Stem Cells Transplantation to Cardiomyogenesis for Functional Regenerative Recovery after Myocardial Infarction

Objective To investigate the dose-dependent relationship of bone marrow mesenchymal stem cells(MSCs) transplantation in improving ischemic myocardial dysfunction? in a rat ischemic heart model. Methods Myocardial infarction was induced in 32 inbred F344 rats by acute ligation of the left anterior descending(LAD) coronary artery. One week after ligation, the ratswere randomized? into four equal groups, with eight rats in each group. Equal volume Iscove’s modified Dulbecco’s medium was injected in the control group, 1×103(group 1), 1×105(group 2), and 1×107(group 3) 5-bromodeoxyuridine (BrdU) labeled bone marrow MSCs were injected into the infarcted myocardium. Cardiac function was evaluated by ultrasound before the ligation of the LAD, before the transplantation and the 4th week after transplantation. The expressions of BrdU,Connexin43,Myosin heavy chain β(MHC), and smooth muscle actin α(α-SMA) were detected by immunofluorescence and immunohistochemistry at the 4th week after transplantation. The amount of functional vessels stained by α-SMA was counted simultaneously. Results At the 4th week? after transplantation, the ejection fraction(EF) in goup 2 was more significantly improved than that in group1(0.54±0.20 vs. 0.34±0.16, P＝0.004) and EF in group 3 was more significantly improved than that in group 2(0.71±0.24 vs. 0.54±0.20,P＝0.018), whereas no significant difference between group 1 and control group was detected (0.34±0.16 vs. 0.36±0.15,Pgt;0.05). The BrdU labeled MSCs could be found in host myocardium. The number of cells in group 2 by double staining both for BrdU and for MHC observed in ischemic myocardium were significantly more than that in group 1? (323.20±91.62 n/HP vs. 51.75±27.58 n/HP,P＝0.049) and the same was true between group 3 and group 2(409.75±106.65 n/HP vs. 323.20±91.62 n/HP,Plt;0.001), whereas the result of control group was negative.The majority of transplanted cells were found positive staining both for MHC and for Connexin43 in all groups. There were lots of positive staining of α-SMA whose form were partly irregular in ischemic myocardium indicating that there was neovascularization in group1 and control group. More neovascularization in group2 was found than that in group 1 (28.38±12.79 n/HP vs. 22.75±9.07 n/HP, P＝0015) and more neovascularization in group 3 was found? than that in group 2 (35.63±13.27 n/HP vs. 28.38±12.79 n/HP, P＝0.002) . Conclusion Transplanted into infarcted myocardium, bone marrow MSCs may have significant and dose-dependent potential for cardiomyogenesis with functional recovery from myocardial ischemia.