Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair
Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair
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DOI：
10.1161/01.res.0000244687.97719.4f
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发表时间：
2006-09-29
影响因子：
20.1
通讯作者：
Ashraf, Muhammad
中科院分区：
文献类型：
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作者：
Jiang, Shujia;Haider, Husnain Kh.;Ashraf, Muhammad
Akt是血管生成素-1 (ang1)/Tie-2信号通路下游的主要细胞存活和血管生成介质。我们假设移植共过表达Ang-1和Akt的间充质干细胞（MSCs）可改善预后。通过腺病毒将ang1和Akt基因转染到雄性Fischer大鼠的MSCs中。通过将细胞暴露于缺氧8小时来评估转基因过表达在体外的细胞保护作用。TUNEL和乳酸脱氢酶检测显示，与未转导的MSCs或仅转导Ang-1或Akt的MSCs相比，共过表达Ang-1和Akt的MSCs （MAAs）对缺氧的抗性更强。在体内研究中，永久性冠状动脉闭塞后，将动物分组（n = 20/组），接受70 μ L不含细胞的基础培养基（1组）或含有3 × 10(6)个非转导MSCs（2组）或MAAs（3组）的心肌内注射。每组4只动物在细胞移植后4、7和14天被安乐死，用于分子研究。第3组MAAs广泛存活，在细胞移植后2周，MAAs在大鼠心脏中继续共过表达转基因。第4周免疫组织学显示供体细胞在移植物部位出现肌源性分化。3组梗死区和梗死周区血管密度最高（P < 0.05）。第4周超声心动图显示，与第1、2组相比，第3组的射血分数、缩短分数等心功能指标均有显著改善（P < 0.05）。我们得出结论，在MSC移植过程中，Ang-1和Akt之间的支持性相互作用通过提高细胞存活率、改善血管生成和恢复整体心功能来改善预后。
Akt is a major cell survival and angiogenic mediator downstream of angiopoietin-1 (Ang-1)/Tie-2 signaling pathway. We hypothesize that transplantation of mesenchymal stem cells (MSCs) co-overexpressing Ang-1 and Akt lead to better prognosis. Ang-1 and Akt genes were adenovirally transduced into MSCs from male Fischer rats. Cytoprotective effects of transgene overexpression in vitro were assessed by exposure of cells to 8 hours of anoxia. TUNEL and measurement of lactate dehydrogenase showed that MSCs co-overexpressing Ang-1 and Akt (MAAs) were more resistant to anoxia as compared with the nontransduced MSCs or those transduced with Ang-1 or Akt alone. For in vivo studies, after permanent coronary artery occlusion, animals were grouped (n = 20/group) to receive intramyocardial injections of 70 mu L of basal medium without cells ( group 1) or containing 3 x 10(6) nontransduced MSCs ( group 2) or MAAs ( group 3). Four animals per group were euthanized on 4, 7, and 14 days after cell transplantation for molecular studies. Extensive survival of MAAs was observed in group 3, which continued to co-overexpress transgenes in rat heart at 2 weeks after cell transplantation. Immunohistology at 4 weeks revealed myogenic differentiation of donor cells at the site of cell graft. Blood vessel density was highest in the infarct and periinfarct regions in group 3 (P < 0.05). Echocardiography at 4 weeks showed that heart function indices were significantly improved in group 3 ( P < 0.05), including ejection fraction and fractional shortening as compared with groups 1 and 2. We conclude that supportive interaction between Ang-1 and Akt during MSC transplantation gave better prognosis via enhanced cell survival, improved angiomyogenesis, and restored global cardiac function.