Disturbed angiogenic activity of adipose-derived stromal cells obtained from patients with coronary artery disease and diabetes mellitus type 2.
Disturbed angiogenic activity of adipose-derived stromal cells obtained from patients with coronary artery disease and diabetes mellitus type 2.
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DOI：
10.1186/s12967-014-0337-4
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发表时间：
2014-12-10
影响因子：
7.4
通讯作者：
Parfyonova YV
中科院分区：
文献类型：
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作者：
Dzhoyashvili NA;Efimenko AY;Kochegura TN;Kalinina NI;Koptelova NV;Sukhareva OY;Shestakova MV;Akchurin RS;Tkachuk VA;Parfyonova YV
包括脂肪基质细胞(ADSC)在内的多潜能间充质干细胞(MSC)已成功应用于心血管疾病的治疗。它们的再生潜力被认为是由于其多能性、旁分泌活性和免疫特免性。然而，自体骨髓间充质干细胞治疗心肌缺血的疗效并不理想。我们分析了患有冠心病(CAD)和2型糖尿病(T2 DM)等慢性疾病的患者的ADSC特性是否减弱。对照组(n = 19例)、单纯冠心病组(n = 32例)、冠心病合并T2 DM组(n = 2 8例)。其表型(流式细胞仪)为CD90+/CD73+/CD105+/CD45−/CD31−，具有成脂和成骨分化能力。所有患者的ADSC形态和免疫表型相似，但冠心病和T2 DM患者的ADSC与对照组相比具有更高的增殖活性和更短的端粒。ADSC条件培养液刺激内皮细胞形成毛细血管样管(EA.hy926)，但冠心病组(p = 0.03)和冠心病 + T2 DM组(p = 0.017)的这一作用明显低于对照组。令人惊讶的是，我们发现ADSC分泌的一些促血管生成因子显著增加：血管内皮生长因子和肝细胞生长因子在冠心病患者和肝细胞生长因子以及胎盘生长因子在冠心病 + T2 DM患者中显著增加。在血栓反应蛋白-1、内皮抑素和纤溶酶原激活物抑制物-1等血管生成抑制物中，冠心病组和冠心病组 + -T2 DM患者条件培养液中纤溶酶原激活物抑制物-1的水平显著高于对照组(p <； )。用中和抗体抑制ADSC条件培养液中的纤溶酶原激活物-1部分恢复了ADSC的血管生成活性(p = 0.017)。在冠心病和T2 DM患者中，ADSC血管生成活性显著降低，这可能限制了自体ADSC细胞治疗在这些队列患者中的有效性。这种损害可能是由于ADSC分泌的促血管生成生长因子和抗血管生成生长因子的协调网络紊乱所致。冠心病和2型糖尿病患者ADSC分泌组的变化不同，需要进一步研究以揭示MSC参与心血管和代谢性疾病的机制，并利用再生医学的方法开发纠正这些疾病的新方法。本文的在线版本(doi：10.1186/s12967-0140337-4)包含补充材料，授权用户可以使用。
Multipotent mesenchymal stem/stromal cells (MSC) including adipose-derived stromal cells (ADSC) have been successfully applied for cardiovascular diseases treatment. Their regenerative potential is considered due to the multipotency, paracrine activity and immunologic privilege. However, therapeutic efficacy of autologous MSC for myocardial ischemia therapy is modest. We analyzed if ADSC properties are attenuated in patients with chronic diseases such as coronary artery disease (CAD) and diabetes mellitus type 2 (T2DM). ADSC were isolated from subcutaneous fat tissue of patients without established cardiovascular diseases and metabolic disorders (control group, n = 19), patients with CAD only (n = 32) and patients with CAD and T2DM (n = 28). ADSC phenotype (flow cytometry) was CD90+/CD73+/CD105+/CD45−/CD31− and they were capable of adipogenic and osteogenic differentiation. ADSC morphology and immunophenotype were similar for all patients, but ADSC from patients with CAD and T2DM had higher proliferation activity and shorter telomeres compared to control patients. ADSC conditioned media stimulated capillary-like tubes formation by endothelial cells (EA.hy926), but this effect significantly decreased for patients with CAD (p = 0.03) and with CAD + T2DM (p = 0.017) compared to the control group. Surprisingly we revealed significantly higher secretion of some pro-angiogenic factors (ELISA) by ADSC: vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) for patients with CAD and HGF and placental growth factor (PlGF) for patients with CAD + T2DM. Among angiogenesis inhibitors such as thrombospondin-1, endostatin and plasminogen activator inhibitor-1 (PAI-1) level of PAI-1 in ADSC conditioned media was significantly higher for patients with CAD and CAD + T2DM compared to the control group (p < 0.01). Inhibition of PAI-1 in ADSC conditioned media by neutralizing antibodies partially restored ADSC angiogenic activity (p = 0.017). ADSC angiogenic activity is significantly declined in patients with CAD and T2DM, which could restrict the effectiveness of autologous ADSC cell therapy in these cohorts of patients. This impairment might be due to the disturbance in coordinated network of pro- and anti-angiogenic growth factors secreted by ADSC. Changes in ADSC secretome differ between patients with CAD and T2DM and further investigation are necessary to reveal the MSC-involved mechanisms of cardiovascular and metabolic diseases and develop novel approaches to their correction using the methods of regenerative medicine. The online version of this article (doi:10.1186/s12967-014-0337-4) contains supplementary material, which is available to authorized users.