Yamahara K, Min K D, Tomoike H, Kangawa K, Kitamura S, Nagaya N
Department of Regenerative Medicine & Tissue Engineering, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka, Japan.
Heart. 2009 Feb;95(4):283-9. doi: 10.1136/hrt.2008.152223. Epub 2008 Dec 18.
Recently, a clinical trial was initiated to evaluate the efficacy of transendocardial transplantation of autologous bone marrow-derived mesenchymal stem cells (MSC) for the treatment of heart failure (HF). Because some HF patient-derived sera did not induce proliferation of autologous MSC, the present study aimed to elucidate humoral factors in sera that attenuate MSC activation and to investigate the role of these humoral factors in the pathogenesis of HF.
Inhibitory effects present in serum were analysed by culturing human MSC with sera from 10 HF patients (FS <25%, BNP >100 pg/ml) and four healthy control subjects. Among the patients, two sera from HF patients showed significant inhibitory activity on MSC proliferation. Protein array and ELISA analysis revealed that these sera contained high levels of angiostatin as well as the active form of matrix metalloproteinase (MMP)-9, which generates angiostatin. Angiostatin significantly inhibited the proliferation and migration of cultured human MSC and increased their apoptosis in a dose-dependent manner. In a rat HF model, serum levels of angiostatin and MMPs increased, but treatment with an MMP inhibitor suppressed these increases.
The results suggest that angiostatin, which can attenuate the activity of MSC, might play a role in the progression of HF.
最近开展了一项临床试验，以评估经心内膜移植自体骨髓间充质干细胞（MSC）治疗心力衰竭（HF）的疗效。由于一些HF患者来源的血清不能诱导自体MSC增殖，本研究旨在阐明血清中减弱MSC激活的体液因子，并研究这些体液因子在HF发病机制中的作用。
通过将人MSC与10例HF患者（FS<25%，BNP>100 pg/ml）和4例健康对照者的血清进行培养，分析血清中的抑制作用。在这些患者中，2例HF患者的血清对MSC增殖具有显著抑制活性。蛋白质芯片和ELISA分析显示，这些血清中含有高水平的血管抑素以及产生血管抑素的基质金属蛋白酶（MMP）-9活性形式。血管抑素以剂量依赖方式显著抑制培养的人MSC的增殖和迁移，并增加其凋亡。在大鼠HF模型中，血管抑素和MMPs的血清水平升高，但用MMP抑制剂治疗可抑制这些升高。
结果表明，可减弱MSC活性的血管抑素可能在HF进展中起作用。
