[Bone marrow stem cells-based SERCA2a gene therapy for heart failure after acute myocardium infarction].

OBJECTIVE: Explore the possibility of MSC to be used to target delivery of therapeutic gene and evaluate the therapeutic effects among gene therapy, MSC transplantation and MSC-based gene therapy. METHODS: MSC were infected with an adenoviral expression vector carrying SERCA2a. SD female rats were used to make animal model with heart failure after AMI and divided into 4 groups randomly. Group I (n = 7) received SERCA2a gene therapy, group II (n = 7) received MSC transplantation, group III (n = 8) received MSC infected with SERCA2a gene transplantation, and group IV (n = 7) received empty adenoviral vector. Cardiac function was evaluated by echocardiography and physiological recorder. SERCA2a gene and protein expression were evaluated by RT-PCR and Western blot respectively. RESULTS: Compared to group IV, EF and FS of group I, group II and group III were elevated significantly on 14 days after therapy (EF: 67.7 +/- 3.9, 62.6 +/- 4.0, 67.9 +/- 3.7 versus 45.0 +/- 2.2; FS: 33.9 +/- 1.9, 31.1 +/- 2.0, 33.9 +/- 1.9 versus 22.5 +/- 1.1, P < 0.05). While the elevation values of EF and FS began to reduce in group I 14 days after, it continued to increase in both group II and group III. Absolute value of LVEDP at 21 days after treatment was increased in group I, group II and group III compared to group IV (5.3 mm Hg +/- 1.2 mm Hg, 6.0 +/- 1.3 mm Hg, 6.2 mm Hg +/- 1.2 mm Hg versus 1.5 mm Hg +/- 0.2 mm Hg, P < 0.05), as well as absolute value of DP/dtmin (4756 mm Hg/s +/- 270 mm Hg/s, 5028 mm Hg/s +/- 253 mm Hg/s, 5283 mm Hg/s +/- 363 mm Hg/s versus 3201 mm Hg/s +/- 211 mm Hg/s, P < 0.05). DP/dtmax at 21 days after treatment increased in group I, group II and group III compared to group IV (6026 mm Hg/s +/- 281 mm Hg/s, 6278 mm Hg/s +/- 319 mm Hg/s, 7057 mm Hg/s +/- 389 mm Hg/s versus 5293 mm Hg/s +/- 360 mm Hg/s, P < 0.05). SERCA2a expressions and enzyme activity were significantly stronger in group I and group III than in group II and group IV. CONCLUSION: It showed that all MSC transplantation, SERCA2a gene therapy and MSC-based gene therapy could enhance cardiac function. The recovered heart function continued to improve in MSC transplantation group and MSC-based gene therapy group up to 21 days, however slowed down in single gene therapy group in 21 days. Such therapeutic tendency of MSC-based gene therapy was stronger than that of MSC transplantation. Thus, MSC proved an effective platform for the targeted delivery of therapeutic gene.

[Bone marrow mesenchymal cell transplantation reduces left ventricular remodeling in heart failure following acute myocardial infarction].

OBJECTIVE: Bone marrow mesenchymal cell (MSC) transplantation has been shown to improve heart failure but the mechanism and the subsequent effects are unclear. We tested the hypothesis that MSC transplantation reduces left ventricular remodeling through the MMP/TIMP system in heart failure following acute myocardial infarction. METHODS: Female SD rats underwent coronary artery ligation to induce myocardial infarction. Four weeks later, the rats were divided into the test group (n = 7) and the control group (n = 7), respectively. The donor MSCs were harvested and expanded from male SD rats (5 x 10(6) in 50 microl PBS) and injected into the ischemic myocardium, while the control group received the same volume of PBS. Left ventricular morphology was then evaluated in both groups through staining with H&E and Masson's trichrome. Immunohistochemical staining was used to examine the expressions of MMP2 and TIMP1, as well as type I and type III collagens, in the scar zones. The protein levels of MMP2 and TIMP1 were determined by Western blotting. RESULTS: MSC differentiated into fibroblast-like cells at 21 days after transplantation in the test group. In addition, many inflammatory cells infiltrated and aggregated in the scar area, but this effect was reduced at day 7 after transplantation. The following changes were noted in the test group compared to the control group: ejection fraction and shortening fraction were higher [(63.43 +/- 3.97)% vs. (36.20 +/- 3.99)%, (31.71 +/- 1.98)% vs. (18.00 +/- 2.07)%, P < 0.05]; dp/dt(min) was reduced [(-4756.24 +/- 270.00) mm Hg/s vs. -2789.53 +/- 624.13) mm Hg/s, P < 0.05]; the left ventricular thinning ratio was significantly higher [(76.34 +/- 2.66)% vs. (64.37 +/- 2.36)%, P < 0.05]; the infarct size was smaller [(36.19 +/- 0.83)% vs. (42.12 +/- 1.88)%, P < 0.05]; type I collagen expression in the scar area was much higher; type III collagen expression was much lower; MMP2 expression was reduced and TIMP1 expression was increased. CONCLUSION: MSC transplantation led to dynamic changes in the collagen network through regulation of MMP2/TIMP1 system and consequently interrupted the progress of adverse LV remodeling in heart failure following acute myocardial infarction.