在转化的绵羊心肌梗死模型中对工程化干细胞趋化因子基质细胞衍生因子 1α类似物的临床前评估。
Preclinical evaluation of the engineered stem cell chemokine stromal cell-derived factor 1α analog in a translational ovine myocardial infarction model.
机构信息
From the Division of Cardiovascular Surgery, Department of Surgery (J.W.M., J.E.C., J.R.M., A.T., A.S.F., G.H., W.H., A.B.G., P.A., J.H.G., R.C.G.), Gorman Cardiovascular Research Group, Department of Surgery (J.R.M., J.J.P., J.H.G., R.C.G.), Division of Interventional Cardiology, Department of Medicine (R.L.W.), and Department of Radiology (J.J.P.), University of Pennsylvania School of Medicine, Philadelphia; and Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA (J.W.M., J.E.C., Y.S., J.B.P., B.B.E., Y.J.W.).
出版信息
Circ Res. 2014 Feb 14;114(4):650-9. doi: 10.1161/CIRCRESAHA.114.302884. Epub 2013 Dec 23.
RATIONALE
After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile.
OBJECTIVE
To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility.
METHODS AND RESULTS
Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01).
CONCLUSIONS
The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.
背景
心肌梗死后，心肌的血液供应不足，周围的边缘区变得收缩无力。
目的
为了开发一种临床可转化的治疗方法，我们假设在心肌梗死的羊前临床模型中，改良的内皮祖细胞趋化因子、工程基质细胞衍生因子 1α 类似物（ESA）将诱导内皮祖细胞趋化，限制不良的心室重构，并保持边缘区的收缩力。
方法和结果
36 只成年雄性 Dorset 绵羊进行了左前降支冠状动脉的永久性结扎，导致前壁和心尖梗死，并随机接受边缘区注射盐水（n=18）或 ESA（n=18）。使用心脏 MRI 和压力-容积导管转换评估心室功能、几何形状和局部应变。采集骨髓进行体外分析，并取心肌活检进行 mRNA、蛋白质和免疫组织化学分析。ESA 诱导的内皮祖细胞趋化作用大于盐水（P<0.01），与重组基质细胞衍生因子 1α 相当（P=0.27）。ESA 治疗动物的 mRNA 表达和蛋白质水平分析显示，边缘区的基质金属蛋白酶 2 减少（P<0.05），梗死区的基质金属蛋白酶 1 组织抑制剂和弹性蛋白水平升高（P<0.05），而 ESA 组边缘区心肌的免疫组织化学分析显示，毛细血管和小动脉密度增加（P<0.01）。ESA 治疗组动物的梗死面积也显著减少（P<0.01），边缘区的最大主应变增加（P<0.01），以及收缩末期压力-容积关系的斜率更陡（P=0.01）。
结论
新型生物分子设计的肽 ESA 诱导内皮祖细胞趋化，刺激新血管生成，限制梗死扩张，并保持心肌梗死后绵羊模型的收缩力。
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