IGF-1-Overexpressing Mesenchymal Stem Cells Accelerate Bone Marrow Stem Cell Mobilization via Paracrine Activation of SDF-1α/CXCR4 Signaling to Promote Myocardial Repair
IGF-1-Overexpressing Mesenchymal Stem Cells Accelerate Bone Marrow Stem Cell Mobilization via Paracrine Activation of SDF-1α/CXCR4 Signaling to Promote Myocardial Repair
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DOI：
10.1161/circresaha.108.186742
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发表时间：
2008-11-21
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：
Haider, Husnain Kh;Jiang, Shujia;Ashraf, Muhammad
我们假设过度表达胰岛素样生长因子 (IGF)-1 的间充质干细胞 (MSC) 在梗塞心脏中表现出改善的存活和植入，并通过旁分泌释放基质细胞衍生因子 (SDF)-1 α 促进干细胞募集。大鼠骨髓来源的 MSC 用作非转导的 ((MSCs)-M-Norm) 或用腺病毒无效载体 ((MSCs)-M-Null) 或编码 IGF-1 的载体 (IGF-1MSCs) 转导。在观察 12 天之前，IGF-1MSC 分泌较高的 IGF-1（与 (MSC)-M-Null 相比，P < 0.001）。分子研究揭示了磷酸肌醇 3-激酶、Akt 和 Bcl 的激活。除了 SDF-1 α 的释放与 IGF-1MSC 中 IGF-1 的表达平行外，xL 还抑制糖原合酶激酶 3 beta。对于体内研究，将70μL不含细胞的DMEM（组1）或含有1.5 x 10（6）（MSC）-M-Null（组2）或IGF-1MSC（组3）的DMEM植入永久性冠状动脉闭塞的雌性大鼠模型的心肌内。一周后，大鼠心脏组织（每组 n = 4 只）的免疫印迹显示第 3 组心肌 IGF-1 和磷酸化 Akt 升高，IGF-1MSC 存活率更高（与 (MSCs)-M-Null 相比，P < 0.06）（每组 n = 6 只）。第 3 组动物心脏中的 SDF-1 α 增加（与第 2 组相比增加了 20 倍），其中 ckit(+)、MDR1(+)、CD31(+) 和 CD34(+) 细胞大量动员并归巢到梗塞心脏中。与对照组相比，细胞移植组的梗塞面积显着减小。肌球蛋白重链、肌动蛋白、连接蛋白-43 和冯维勒布兰德因子 VIII 免疫染色后的共聚焦成像显示梗塞心脏中广泛的血管肌生成。与第1组相比，第3组的左心室功能指数（包括射血分数和缩短分数）有所改善（P < 0.05）。总之，IGF-1 转基因表达策略通过 SDF-1 α 信号传导诱导大量干细胞动员，最终导致梗塞心脏中广泛的血管肌生成。 （Circ Res. 2008；103：1300-1308。）
We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1 alpha. Rat bone marrow-derived MSCs were used as nontransduced ((MSCs)-M-Norm) or transduced with adenoviral-null vector ((MSCs)-M-Null) or vector encoding for IGF-1 (IGF-1MSCs). IGF-1MSCs secreted higher IGF-1 until 12 days of observation (P < 0.001 versus (MSCs)-M-Null). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl. xL and inhibition of glycogen synthase kinase 3 beta besides release of SDF-1 alpha in parallel with IGF-1 expression in IGF-1MSCs. For in vivo studies, 70 mu L of DMEM without cells (group 1) or containing 1.5 x 10(6) (MSCs)-M-Null (group 2) or IGF-1MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n = 4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of IGF-1MSCs (P < 0.06 versus (MSCs)-M-Null) (n = 6 per group). SDF-1 alpha was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P < 0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1 alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart. (Circ Res. 2008; 103: 1300-1308.)