Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines
Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines
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DOI：
10.1161/hc3501.093817
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发表时间：
2001-08-28
期刊：
影响因子：
37.8
通讯作者：
Iwasaka, T
中科院分区：
文献类型：
--
作者：
Kamihata, H;Matsubara, H;Iwasaka, T
背景-骨髓移植（BMT）被证明可以增强大鼠缺血性心脏模型的血管生成。这项使用猪模型的临床前研究旨在测试 BMI 的安全性和治疗效果。方法和结果 - 将 BM 衍生的单核细胞 (BM-MNC) 注射到通过冠状动脉结扎造成缺血的区域。 BMI 三周后，局部血流量和毛细血管密度显着升高（分别是 4.6 倍和 2.8 倍），心功能也得到改善。血管造影显示可见侧支血管数量显着增加（5.7 倍）。猪冠状动脉微血管内皮细胞（CMEC）的植入并未引起毛细血管密度的任何显着增加。标记的 BM-MNC 被纳入约 31% 的新毛细血管中，并对应于约 8.7% 的巨噬细胞，但并未作为成肌细胞或成纤维细胞积极存活。没有成骨细胞形成骨或恶性室性心律失常。 BMI、CMEC 和单独介质植入组之间心肌酶（肌钙蛋白 I 和肌酸激酶-MB）血浆水平随时间的变化没有差异。 BM-MNC 含有 16% 的内皮细胞谱系，表达的碱性成纤维细胞生长因子远高于血管内皮生长因子 > 血管生成素 1 mRNA，并且 BMI 显着上调其心脏水平。 BMI 也可诱导心脏白细胞介素 1 β 和肿瘤坏死因子 α mRNA 表达，但 CMEC 植入则不会诱导该表达。 BM-MNCs在体外积极分化为内皮细胞，并与人脐静脉内皮细胞形成网络结构。结论-BMI可能构成一种新的安全策略，通过BM细胞分泌强效血管生成配体和细胞因子以及掺入新生血管形成灶的天然能力来实现最佳治疗性血管生成。
Background-Bone marrow implantation (BMT) was shown to enhance angiogenesis in a rat ischemic heart modal. This preclinical study using a swine model was designed to test the safety and therapeutic effectiveness of BMI.Methods and Results-BM-derived mononuclear cells (BM-MNCs) were injected into a zone, made ischemic by coronary artery ligation. Three weeks after BMI, regional blood flow and capillary densities were significantly higher (4.6- and 2.8-fold, respectively), and cardiac function was improved. Angiography revealed that there was a marked increase (5.7-fold) in number of visible collateral vessels. Implantation of porcine coronary microvascular endothelial cells (CMECs) did not cause any significant increase in capillary densities. Labeled BM-MNCs were incorporated into approximate to 31% of neocapillaries and corresponded to approximate to8.7% of macrophages but did not actively survive as myoblasts or fibroblasts. There was no bone formation by osteoblasts or malignant ventricular arrhythmia. Time-dependent changes in plasma levels for cardiac enzymes (troponin I and creatine kinase-MB) did not differ between the BMI, CMEC, and medium-alone implantation groups. BM-MNCs contained 16% of endothelial-lineage calls and expressed basic fibroblast growth factor much greater than vascular endothelial growth factor>angiopoiatin 1 mRNAs, and their cardiac levels were significantly upregulated by BMI. Cardiac interleukin-1 beta and tumor necrosis factor-alpha mRNA expression were also induced by BMI but not by CMEC implantation. BM-MNCs were actively differentiated to endothelial cells in vitro and formed network structure with human umbilical vein endothelial calls.Conclusions-BMI may constitute a novel safety strategy for achieving optimal therapeutic angiogenesis by the natural ability of the BM cells to secrete potent angiogenic ligands and cytokines as well as to be incorporated into foci of neovascularization.