Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation.
Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation.
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DOI：
10.1371/journal.pone.0005643
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发表时间：
2009-05-21
期刊：
影响因子：
3.7
通讯作者：
Kalka C
中科院分区：
文献类型：
--
作者：
Di Santo S;Yang Z;Wyler von Ballmoos M;Voelzmann J;Diehm N;Baumgartner I;Kalka C
目前的证据表明，内皮祖细胞(EPC)通过分泌旁分泌因子和掺入发育中的血管而促进缺血组织的修复。我们验证了这样一种假设，即无细胞给药培养的EPC分泌的旁分泌因子可能达到与细胞治疗相同的血管生成效果。培养扩增后的EPC经72小时缺氧处理，获得EPC衍生条件培养液(EPC-CM)。在体外，EPC-CM显著抑制成熟内皮细胞的凋亡，并促进血管生成。在慢性后肢缺血大鼠模型上，评估了EPC-CM与EPC移植的治疗潜力。连续肌肉注射EPC-CM和EPC均显著增加激光多普勒测定的后肢血流量(81.2±2.9%和83.7±3.0%比正常的53.5±2.4%，P<；0.01)，并改善肌肉功能。毛细血管密度(1.62±0.03和1.68±0.05/肌纤维，P<；0.05)、血管成熟度(8.6±0.3和8.1±0.4/HPF，P<；0.05)和肌肉活力显著增加，证实了后肢血流灌注和肌肉功能的改善。此外，EPC-CM移植组在最后一次注射后3天刺激了骨髓来源的EPC的动员(678.7±44.1vs.340.0±29.1CD34+/CD45HPF细胞/1×10~5单核细胞，P；0.001)和它们在缺血肌中的募集(5.90±0.7vs.2.6±0.4CD34+细胞/−，P<；0.001)。肌肉注射EPC-CM在促进组织血运重建和功能恢复方面与细胞移植一样有效。由于细胞治疗的技术和实践的局限性，无细胞条件培养液可能成为治疗缺血性心血管疾病血管生成的有效选择。
Current evidence suggests that endothelial progenitor cells (EPC) contribute to ischemic tissue repair by both secretion of paracrine factors and incorporation into developing vessels. We tested the hypothesis that cell-free administration of paracrine factors secreted by cultured EPC may achieve an angiogenic effect equivalent to cell therapy. EPC-derived conditioned medium (EPC-CM) was obtained from culture expanded EPC subjected to 72 hours of hypoxia. In vitro, EPC-CM significantly inhibited apoptosis of mature endothelial cells and promoted angiogenesis in a rat aortic ring assay. The therapeutic potential of EPC-CM as compared to EPC transplantation was evaluated in a rat model of chronic hindlimb ischemia. Serial intramuscular injections of EPC-CM and EPC both significantly increased hindlimb blood flow assessed by laser Doppler (81.2±2.9% and 83.7±3.0% vs. 53.5±2.4% of normal, P<0.01) and improved muscle performance. A significantly increased capillary density (1.62±0.03 and 1.68±0.05/muscle fiber, P<0.05), enhanced vascular maturation (8.6±0.3 and 8.1±0.4/HPF, P<0.05) and muscle viability corroborated the findings of improved hindlimb perfusion and muscle function. Furthermore, EPC-CM transplantation stimulated the mobilization of bone marrow (BM)-derived EPC compared to control (678.7±44.1 vs. 340.0±29.1 CD34+/CD45− cells/1×105 mononuclear cells, P<0.05) and their recruitment to the ischemic muscles (5.9±0.7 vs. 2.6±0.4 CD34+ cells/HPF, P<0.001) 3 days after the last injection. Intramuscular injection of EPC-CM is as effective as cell transplantation for promoting tissue revascularization and functional recovery. Owing to the technical and practical limitations of cell therapy, cell free conditioned media may represent a potent alternative for therapeutic angiogenesis in ischemic cardiovascular diseases.
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影响因子：
5
作者：
Jujo, Kentaro;Ii, Masaaki;Losordo, Douglas W.
通讯作者：
Losordo, Douglas W.
影响因子：
37.8
作者：
Hofmann, M;Wollert, KC;Drexler, H
通讯作者：
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影响因子：
82.9
作者：
Chen, JH;Somanath, PR;Byzova, TV
通讯作者：
Byzova, TV
影响因子：
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作者：
JAFFE, EA;NACHMAN, RL;MINICK, CR
通讯作者：
MINICK, CR
DOI：
10.1016/s0735-1097(00)00882-2
发表时间：
2000-10-01
影响因子：
24
作者：
Lazarous, DF;Unger, EF;Quyyumi, AA
通讯作者：
Quyyumi, AA