金培峰
中国医学科学院阜外医院 再生医学实验室
The purpose of this study was to investigate the fate of transplanted cells in the central zone of myocardial infarction (MI), and to clarify the relationship between the injection-site impact and the efficacy of cell therapy. MI was created by coronary ligation in female rats. Three weeks later, 3-million labelled male bone marrow mesenchymal stem cells (BMSCs) were directly injected into the border (BZC group) or central zone (CZC group) of MI area. As a control, culture medium was injected into the same sites. Cell survival was evaluated by quantitative real-time polymerase chain reaction, and apoptosis was assayed with TUNEL and caspase-3 staining. Four weeks after transplantation, heart function and cardiac morphometry were evaluated by echocardiography and Masson's Trichrome staining, respectively. Angiogenesis and myogenesis were detected by immunofluorescence staining. After cell transplantation into the border or central zone, there was no cell migration between the different zones of MI. BMSCs in the CZC group exhibited no difference in apoptotic percentage, in the long-term survival, when compared with those in the BZC group. However, they did effectively promote angiogenesis and cellular myogenic differentiation. Although cell delivery in the central zone of MI had no effect on the recovery of heart function compared with the BZC group, the retained BMSCs could still increase the scar thickness, and subsequently exhibit a trend in the reverse remodelling of ventricular dilation. Hence, we concluded that the central zone of MI should not be ignored during cell-based therapy. Multiple site injection (border+central zone) is strongly recommended during the procedure of cell transplantation.
Journal of cellular and molecular medicine 2012
AIMS:Intravenous administration of bone marrow mesenchymal stromal cells (MSCs) is an attractive option for the treatment of myocardial infarction (MI). Previous studies revealed that MSC infusion could limit the deterioration of cardiac function following acute MI; however, little is known regarding the safety and efficacy of MSC infusion for chronic MI. In this study, we address cell retention after intravenous injection in a chronic MI model, and the fate and impact of distributed MSCs in the lung and heart.METHODS:MI model was created by coronary ligation in female rats. A total of 3 weeks later, 5 × 10(6) bromodeoxyuridine-labeled male MSCs in 300 µl phosphate-buffered solution (PBS) were infused intravenously (cell transplantation group, n = 37). The same volume of PBS was infused and served as the control group (n = 37). A total of 20 healthy rats received intravenous PBS injections and served as the sham group. 1 day and 4 weeks after cell or PBS infusion, echocardiography was performed and cell retention was evaluated by quantitative real-time PCR. The fate of the migrated cells was detected through immunohistochemistry and the expression of inflammatory and anti-inflammatory protein was evaluated in lung and heart. The lung and heart function was also assessed.RESULTS:1 day after cell implantation, the percentage of retained cells relative to the initial number of injected cells in heart and lung was 0.54 ± 0.19% and 51.69 ± 12.96%, respectively. After 4 weeks, it decreased to 0.24 ± 0.09% and 0.22 ± 0.17%. The entrapped MSCs did not differentiate into alveolar epithelial-like cells. Likewise, the left ventricular function was not improved. No adverse effects on lung function were observed after cell infusion. The expression of pro-inflammatory factors, including TNF-α, IL-1β, malondialdehyde and myeloperoxidase, and anti-inflammatory factors, including TNF-α-induced protein 6, in the lung and heart was not significantly regulated after cell transplantation.CONCLUSION:Although the majority of intravenous infused cells were harbored in the lung, they did not cause deterioration of lung function. However, they did not activate the release of inflammatory/anti-inflammatory proteins, or stimulate angiogenesis or myogenesis in the old infarcted myocardium. Thus, intravenous administration of MSCs for chronic MI needs further experimental study.
Regenerative medicine 2011
BACKGROUND:Neural remodeling after myocardial infarction (MI) may cause fatal ventricular arrhythmia. Schwann cells (SCs), which are important for neurogenesis, are dramatically reduced after MI. We investigated the feasibility of modifying nervous system regeneration after MI and the efficacy by which it may prevent ventricular arrhythmia following SC transplantation.METHODS AND RESULTS:Immediately after creation of MI, syngenic Lewis rats were randomized into cell transplantation (n=80) and control groups (n=72). SCs were isolated from sciatic nerves, and 5×10(6) cells were intramyocardially injected into the infarct region. Expression levels of myocardial nerve growth factor, vascular endothelial growth factor, growth-associated protein 43, connexin 43, and laminin in the SC group were significantly higher than control at 7 and 14 days after cell transplantation. Immunohistochemical staining illustrated increases in sympathetic and parasympathetic nerves in both groups. However, SC transplantation significantly increased the parasympathetic/sympathetic ratio at 14 days after cell injection. Dynamic electrocardiography and programmed electric stimulation were also performed. The SCs significantly decreased the low-/high-frequency ratio and arrhythmia score of programmed electric stimulation-induced ventricular arrhythmia at 2 weeks after cell injection. However, SCs did not restore heart function.CONCLUSIONS:Transplanted SCs in the infarcted myocardium secrete multiple biological molecules, which alter the ratio of parasympathetic/sympathetic nerve density to normalize irritable myocardium. SC transplantation might be a novel cell-based antiarrhythmic therapy following MI.
Circulation 2010
