Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA.
Am J Physiol Heart Circ Physiol. 2010 Dec;299(6):H1772-81. doi: 10.1152/ajpheart.00557.2010. Epub 2010 Sep 24.
Transplanted mesenchymal stem cells (MSC) release soluble factors that contribute to cardiac repair and vascular regeneration. We hypothesized that overexpression of GATA-4 enhances the MSC secretome, thereby increasing cell survival and promoting postinfarction cardiac angiogenesis. MSCs harvested from male rat bone marrow were transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus retroviral expression system; control cells were either nontransduced (MSC(bas)) or transduced with empty vector (MSC(Null)). Compared with these control cells, MSC(GATA-4) were shown by immunofluorescence, real-time PCR, and Western blotting to have higher expression of GATA-4. An increased expression of angiogenic factors in MSC(GATA-4) and higher MSC resistance against hypoxia were observed. Human umbilical vein endothelial cells (HUVEC) treated with MSC(GATA-4) conditioned medium exhibited increased formation of capillary-like structures and promoted migration, compared with HUVECs treated with MSC(Null) conditioned medium. MSC(GATA-4) were injected into the peri-infarct region in an acute myocardial infarction model in Sprague-Dawley rats developed by ligation of the left anterior descending coronary artery. Survival of MSC(GATA-4), determined by Sry expression, was increased at 4 days postengraftment. MSC(GATA-4)-treated animals showed significantly improved cardiac function as assessed by echocardiography. Furthermore, fluorescent microsphere and histological studies revealed increased blood flow and blood vessel density and reduced infarction size in MSC(GATA-4)-treated animals. We conclude that GATA-4 overexpression in MSCs increased both MSC survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct remodeling.
移植的间充质干细胞 (MSC) 释放可溶性因子，有助于心脏修复和血管再生。我们假设过表达 GATA-4 会增强 MSC 的分泌组，从而提高细胞存活率并促进梗死后的心脏血管生成。使用鼠干细胞病毒逆转录病毒表达系统，从雄性大鼠骨髓中收获 MSC 并转导 GATA-4（MSC(GATA-4)）；对照细胞要么未转导（MSC(bas)），要么转导空载体（MSC(Null)）。通过免疫荧光、实时 PCR 和 Western blot 检测，与这些对照细胞相比，MSC(GATA-4)的 GATA-4 表达更高。观察到 MSC(GATA-4)中血管生成因子的表达增加和对缺氧的更高抵抗性。用 MSC(GATA-4)条件培养基处理的人脐静脉内皮细胞 (HUVEC) 与用 MSC(Null)条件培养基处理的 HUVEC 相比，毛细血管样结构的形成增加，迁移能力增强。将 MSC(GATA-4)注射到结扎左前降支冠状动脉建立的急性心肌梗死模型的梗死周围区。通过 Sry 表达确定 MSC(GATA-4)的存活在植入后 4 天增加。通过超声心动图评估，MSC(GATA-4)治疗的动物显示出心脏功能明显改善。此外，荧光微球和组织学研究显示，MSC(GATA-4)治疗的动物的血流和血管密度增加，梗塞面积减小。我们得出结论，GATA-4 在 MSC 中的过表达增加了缺血心肌中 MSC 的存活和血管生成潜能，因此可能代表一种新的有效的梗死后重塑治疗方法。
