Cell Transplantation for the Treatment of Acute Myocardial Infarction Using Vascular Endothelial Growth Factor-Expressing Mesenchymal Stem Cells

血管内皮生长因子(VEGF)可能通过诱导血管生成而成为治疗缺血区的药物。间充质干细胞(MSCs)具有包括心肌细胞在内的多种分化潜能。因此，我们推测，移植表达血管内皮生长因子的骨髓间充质干细胞可以通过提供血管内皮生长因子诱导的心肌保护、缺血心肌的血管生成以及骨髓间充质干细胞来源的细胞的功能优势来有效地治疗心肌梗死。用低糖DMEM培养Lewis大鼠骨髓单个核细胞，观察MSCs的生长情况。将表达人血管内皮生长因子165和/或β-半乳糖苷酶(lac-Z)的腺病毒导入MSCs。将600万只经血管内皮细胞生长因子(VEGF)和lac Z基因转染的MSCs(n=8)、转lac Z基因的MSCs(n=7)或单纯中膜组(M组，n=10)注入同系大鼠左冠状动脉闭塞1h后的心肌梗死内。注射后1周，Lac Z表达细胞免疫…VEGF组和CONT组的化学检测结果较多。此外，VEGF多克隆抗体阳性率高于CONT组。4周时，VEGE组较M组梗死面积显著缩小(VEG26.3，Cont；31.4，M；38.0%，P&lt；0.05)。经超声心动图评估，血管内皮生长因子组左室舒张末期内径明显小于M组(血管内皮生长因子9.9，常数10.2，男性10.8 mm，p&lt；0.01)。左心室短轴缩短率(VEGF；20.0，Cont；17.7，M；10.7%，P&lt；0.05)和射血分数(VEGF；48.3，Cont；43.6，M；28.6%，P&lt；0.05)在两组间差异有统计学意义。光镜下可见VEGF组梗死区毛细血管增多。在电子显微镜下，VEGF组和Cont组梗死区附近均可见大量梭形间质细胞和含有肌丝的小细胞。此外，在VEGF组中，梭形细胞之间经常点到点接触，并在管腔周围螺旋状排列。综上所述，细胞移植与基因治疗相结合的策略对急性心肌梗死的治疗具有重要意义。较少

Vascular endothelial growth factor (VEGF) may be a therapeutic reagent for ischemic region by inducing angiogenesis. Mesenchymal stem cells (MSCs) have multiple differentiated potential including cardiomyocytes. Therefore, we hypothesized that transplantation of VEGF-expressing MSCs could effectively treat myocardial infarction by providing VEGF-induced cardioprotection, followed by angiogenesis in ischemic myocardium combined with the functional benefits of MSCs-derived cells. Bone marrow mononuclear cells of Lewis rats were cultured with low glucose DMEM for MSCs outgrowth. MSCs were transfected with adenovirus expressing human VEGF_<165> and/or beta-galactosidase (lac Z). Six million of VEGF and lac Z transfected MSCs (VEGF group, n=8), lac Z transfected MSCs (Cont group, n=7), or medium only (M group, n=10) were injected into infarcted myocardium of syngeneic rat after left coronary artery occlusion for one hour. At one week after the injection, lac Z-expression cells were immunohi … More stochemically detected in VEGF group and Cont group. Moreover, positive finding against VEGF polyclonal antibody was increased in VEGF group than in Cont group. At four weeks, infarct size (VEGF; 26.3, Cont; 31.4, M; 38.0 %, P<0.05) was significantly reduced in VEGE group, compared with M group. By echocardiography assessment, left ventricular end-diastolic dimension was significantly lower in the VEGF group, compared with M group (VEGF; 9.9, Cont; 10.2, M; 10.8 mm, p<0.01). Left ventricular fractional shortening (VEGF; 20.0, Cont; 17.7, M; 10.7 %, P<0.05) and ejection fraction (VEGF; 48.3, Cont; 43.6, M; 28.6 %, P<0.05) were significantly higher in VEGF group and Cont group. By light microscopy, increased number of capillaries was observed in infarcted area of VEGF group. Under electoron microscopy, many spindle-shaped interstitial cells and small cells containing myofilaments were observed adjacent to the infarcted area both in VEGF group and Cont group. Furthermore, the spindle-shaped cells were often making point-to-point contact each other and arranged helically around a lumen in VEGF group. In conclusion, this combined strategy of cell transplantation with gene therapy could be important for the treatment of acute myocardial infarction. Less