Department of Cardiology, The Affiliated Jiangning Hospital of Nanjing Medical University, and Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, 211100, China.
Mol Biol Rep. 2012 Jan;39(1):285-93. doi: 10.1007/s11033-011-0737-y. Epub 2011 May 7.
Many studies showed beneficial effects of either statin or bone marrow-derived mesenchymal stem cells (MSC) treatment in ischemic disease. In an attempt to further improve postischemic tissue repair, we investigated the effect of a local administration of MSC, in the presence or not of low-dose simvastatin, on angiogenesis and functional recovery in a mouse model of hindlimb ischemia. In vitro, the proliferation, migration, apoptosis, and tube formation of bone marrow MSC derived from transgenic mice expressing green fluorescent protein (GFP) were detected in the presence or not of 0.01 μmol/l simvastatin, respectively. In vivo, immediately after hindlimb ischemia, the mice were divided into four groups, namely control, MSC, statin, and statin-MSC, and received a single local injection of MSC (2×10(6) cells) and/or a repeated gavages' administration of simvastatin (0.2 mg/kg) for 21 days. The blood flow was measured by laser Doppler imaging, the capillary density was detected by alkaline phosphatase staining and, the MSC differentiation was assessed by immunofluorescent staining at 21 days after the ischemia. In vitro, the MSC proliferation rate, migration ability and tube formation number were increased significantly in simvastatin group relative to control group. Whereas, the H2O2 induced-apoptosis was inhibited significantly in simvastatin group relative to control group. In vivo, hindlimb blood reperfusion was significantly improved (MSC 0.55±0.08, statin 0.57±0.05, vs. control 0.47±0.07, P<0.05) and capillary density was obviously higher at day 21 post-ischemia by Laser Doppler Imaging in the MSC group and the Statin group when compared with control group. The combined use of statin and MSC further improved revascularization (perfusion ratio of 0.70±0.09; P<0.001 verse other groups) and resulted in the highest capillary density (P<0.05 vs. all other groups). GFP-labeled transplanted cells were more frequently observed in the Statin-MSC group than in the MSC group (6.8±0.5-3.1±0.7, P<0.05). Low-dose simvastatin could act in a synergistic way with MSC to potentiate the functional neovascularization in a mouse model of hind limb ischemia.
许多研究表明他汀类药物或骨髓间充质干细胞（MSC）治疗对缺血性疾病有益。为了进一步提高缺血后组织修复，我们研究了在存在或不存在低剂量辛伐他汀的情况下，局部给予 MSC 对小鼠后肢缺血模型中血管生成和功能恢复的影响。在体外，检测了表达绿色荧光蛋白（GFP）的转基因小鼠来源的骨髓 MSC 的增殖、迁移、凋亡和管形成，分别在存在或不存在 0.01 μmol/L 辛伐他汀的情况下。在体内，后肢缺血后立即将小鼠分为对照组、MSC 组、辛伐他汀组和辛伐他汀-MSC 组，分别接受单次局部注射 MSC（2×10^6 个细胞）和/或重复给予辛伐他汀（0.2mg/kg）21 天。通过激光多普勒成像测量血流，碱性磷酸酶染色检测毛细血管密度，免疫荧光染色评估 MSC 分化，缺血后 21 天。在体外，与对照组相比，辛伐他汀组 MSC 增殖率、迁移能力和管形成数量明显增加。而辛伐他汀组的 H2O2 诱导的凋亡明显低于对照组。在体内，与对照组相比，后肢血液再灌注明显改善（MSC 组 0.55±0.08，辛伐他汀组 0.57±0.05，vs. 对照组 0.47±0.07，P<0.05），激光多普勒成像显示缺血后第 21 天毛细血管密度明显高于对照组。与对照组相比，辛伐他汀和 MSC 联合使用进一步改善了再血管化（灌注比为 0.70±0.09；P<0.001），并导致了最高的毛细血管密度（P<0.05 vs. 所有其他组）。与 MSC 组相比，在 Statin-MSC 组中观察到更多的 GFP 标记的移植细胞（6.8±0.5-3.1±0.7，P<0.05）。低剂量辛伐他汀与 MSC 以协同方式作用，增强小鼠后肢缺血模型中的功能性新血管生成。
