Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts
Forced myocardin expression enhances the therapeutic effect of human mesenchymal stem cells after transplantation in ischemic mouse hearts
复制标题
DOI：
10.1634/stemcells.2007-0523
复制
发表时间：
2008-04-01
期刊：
影响因子：
5.2
通讯作者：
Atsmaa, Douwe E.
中科院分区：
文献类型：
--
作者：
Grauss, Robert W.;van Tuyn, John;Atsmaa, Douwe E.
人骨髓间充质干细胞（hMSCs）向心肌细胞分化的潜能有限。心肌转录因子myocardin的强制表达可以刺激hMSCs获得心肌表型，从而提高其可能的治疗潜力。用绿色荧光蛋白（GFP）和心肌蛋白（hMSC（myoc））或GFP和空载体（hMSC）转导hMSC。在免疫受损的NOD/scid小鼠中进行冠状动脉结扎后，将hMSC（myoc）（n = 10）、hMSC（n = 10）或仅培养基（n = 12）注射到梗塞区域中。使用假手术小鼠（n = 12）来确定基线特征。左心室（LV）容积和射血分数（EF）连续（第2天和第14天）使用9.4-T磁共振成像进行评估。在第15天进行LV压力-容积测量，然后进行组织学评价。在第2天，心肌梗死组之间的梗死面积、LV体积或EF无差异。在第14天，与未处理组相比，两个细胞处理组中的左心室射血分数得以保留;此外，与培养基注射相比，hMSC（myoc）注射也减少了LV体积（p <0.05）。此外，压力-容积测量结果显示，与hMSC治疗相比，hMSC（myoc）注射后LV功能显著改善。在第15天的免疫组织化学显示，与hMSC组相比，hMSC（myoc）组中的植入率更高（p <0.05）。此外，这些细胞表达了许多在hMSC组中未观察到的心肌细胞特异性标志物。心肌梗死后，注射hMSC myoc改善了LV功能，限制了LV重塑，注射hMSC后未观察到这种效果。此外，强制myocardin的表达提高移植，并诱导心肌样表型hMSC分化。
Human mesenchymal stem cells (hMSCs) have only a limited differentiation potential toward cardiomyocytes. Forced expression of the cardiomyogenic transcription factor myocardin may stimulate hMSCs to acquire a cardiomyogenic phenotype, thereby improving their possible therapeutic potential. hMSCs were transduced with green fluorescent protein (GFP) and myocardin (hMSC(myoc)) or GFP and empty vector (hMSC). After coronary ligation in immune-compromised NOD/scid mice, hMSC(myoc) (n = 10), hMSC (n = 10), or medium only (n = 12) was injected into the infarct area. Sham-operated mice (n = 12) were used to determine baseline characteristics. Left ventricular (LV) volumes and ejection fraction (EF) were serially (days 2 and 14) assessed using 9.4-T magnetic resonance imaging. LV pressure-volume measurements were performed at day 15, followed by histological evaluation. At day 2, no differences in infarct size, LV volumes, or EF were observed among the myocardial infarction groups. At day 14, left ventricular ejection fraction in both cell-treated groups was preserved compared with the nontreated group; in addition, hMSC(myoc) injection also reduced LV volumes compared with medium injection (p < .05). Furthermore, pressure-volume measurements revealed a significantly better LV function after hMSC(myoc) injection compared with hMSC treatment. Immunohistochemistry at day 15 demonstrated that the engraftment rate was higher in the hMSC(myoc) group compared with the hMSC group (p < .05). Furthermore, these cells expressed a number of cardiomyocyte-specific markers not observed in the hMSC group. After myocardial infarction, injection of hMSCmyoc improved LV function and, limited LV remodeling, effects not observed after injection of hMSC. Furthermore, forced myocardin expression improved engraftment and induced a cardiomyocyte-like phenotype hMSC differentiation.