Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization
Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization
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DOI：
10.1038/labinvest.2010.202
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发表时间：
2011-04-01
影响因子：
5
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
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作者：
Sato, Takatoshi;Iso, Yoshitaka;Suzuki, Hiroshi
很少有报道研究成人骨髓多能基质细胞（MSC）对大型动物的影响，并且尚未建立有效的 MSC 植入方法。在这项研究中，我们研究了从冠状静脉输注 MSC 对慢性心肌梗死 (MI) 猪模型的影响。通过将珠子置于左冠状动脉中在家猪中诱导心肌梗死。吸出骨髓细胞，然后培养以分离MSC。 MI后4周，用染料（n - 8）或载体（n - 5）标记的MSC从前室间静脉逆行输注，没有任何并发症。在细胞输注前和细胞输注后 4 周进行左心室造影 (LVG)。对照组的 LVG 评估的射血分数（EF）从基线到随访 4 周显着下降（P < 0.05），而 MSC 组的心功能得到保留。 MSC 组基线和随访期间 EF 的差异显着大于对照组（P < 0.05）。与对照组相比，MSC 给药显着促进了边缘区域的新生血管形成（P < 0.0005），但对心脏纤维化没有影响。在分化试验中，少数 MSC 表达血管性血友病因子，但均不表达肌钙蛋白 T。在定量基因表达分析中，MSC 处理的心脏中碱性成纤维细胞生长因子和血管内皮生长因子 (VEGF) 水平显着高于对照组（分别 P < 0.05）。免疫组织化学染色显示移植的 MSC 中产生 VEGF。体外实验表明，与VEGF蛋白相比，MSCs显着刺激内皮毛细血管网络形成（P < 0.0001）。通过冠状静脉输注 MSC 可预防慢性 MI 中心功能障碍的进展。这种有利的效果似乎不是源自细胞分化，而是源自间充质干细胞分泌的血管生成因子增强的新血管形成。实验室调查 (2011) 91, 553-564; doi：10.1038/labinvest.2010.202； 2011 年 1 月 31 日在线发布
Few reports have examined the effects of adult bone marrow multipotent stromal cells (MSCs) on large animals, and no useful method has been established for MSC implantation. In this study, we investigate the effects of MSC infusion from the coronary vein in a swine model of chronic myocardial infarction (MI). MI was induced in domestic swine by placing beads in the left coronary artery. Bone marrow cells were aspirated and then cultured to isolate the MSCs. At 4 weeks after MI, MSCs labeled with dye (n - 8) or vehicle (n - 5) were infused retrogradely from the anterior interventricular vein without any complications. Left ventriculography (LVG) was performed just before and at 4 weeks after cell infusion. The ejection fraction (EF) assessed by LVG significantly decreased from baseline up to a follow-up at 4 weeks in the control group (P < 0.05), whereas the cardiac function was preserved in the MSC group. The difference in the EF between baseline and follow-up was significantly greater in the MSC group than in the control group (P < 0.05). The MSC administration significantly promoted neovascularization in the border areas compared with the controls (P < 0.0005), though it had no affect on cardiac fibrosis. A few MSCs expressed von Willebrand factor in a differentiation assay, but none of them expressed troponin T. In quantitative gene expression analysis, basic fibroblast growth factor and vascular endothelial growth factor (VEGF) levels were significantly higher in the MSC-treated hearts than in the controls (P < 0.05, respectively). Immunohistochemical staining revealed VEGF production in the engrafted MSCs. In vitro experiment demonstrated that MSCs significantly stimulated endothelial capillary network formation compared with the VEGF protein (P < 0.0001). MSC infusion via the coronary vein prevented the progression of cardiac dysfunction in chronic MI. This favorable effect appeared to derive not from cell differentiation, but from enhanced neovascularization by angiogenic factors secreted from the MSCs. Laboratory Investigation (2011) 91, 553-564; doi:10.1038/labinvest.2010.202; published online 31 January 2011