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ȣ - 500759 23 |
| Augmentation of angiogenic potential of peripheral blood stem cells mobilized with granulocyte-colony stimulating factor by COMP-Ang1 priming. |
| 서울대학교 의과대학 내과학 교실, 서울대학교병원 임상의학연구소 심혈관줄기세포연구실 |
| 김민석, 이춘수(공저자), 허진, 김태연, 전수인, 서정원, 박경우, 이해영, 강현재, 김효수, 손대원, 오병희, 박영배, 최윤식 |
Background : The intracoronary infusion of peripheral blood stem cells(PBSCs) mobilized with G-CSF was reported to improve systolic function in myocardial infarction. However, poor engraftment of PBSCs remains to be solved. Here we showed the priming effects of PBSCs with COMP-Ang1. Methods and Results: COMP-Ang1 was applicated as a priming agent based on the finding that 24.5% of mobilized PBSCs express Tie-2+. Treatment of COMP-Ang1 to PBSCs increased commitment of PBSCs to endothelial lineage. COMP-Ang1 primed PBSCs exhibited more expression of CD31 and VE-cadherin. EPC colony number was also increased by 2 folds(p<0.001). Next, we investigated the action mechanisms of COMP-Ang1. COMP-Ang1 priming increased Ets-1 expression, which was reversed by Tie2 blocking antibody. And increased commitment into endothelial lineage was attenuated with transfection of antisense Ets-1 oligodeoxynucleotides(ODN), which suggested that the effect of COMP-Ang1 was mediated by Tie2-Ets-1 signaling. COMP-Ang1 priming also increased the expression of α4 and α5 integrins, which was attenuated by antisense Ets-1 ODN transfection. COMP-Ang1 priming increased the adhesion of PBSCs onto HUVECs by 2.5 folds and to fibronectin by 1.5 folds, which was reversed both by Tie2 blocking antibody and by anti-integrin antibody, suggesting that the effect of COMP-Ang1 on adhesion was mediated by Tie2-integrin signaling. Next, we evaluated the effect of COMP-Ang1 priming on the engraftment of PBSCs by using rabbit ear ischemia model. We injected PBSCs tagged with Tc-99m HMPAO via rabbit ear central vessel and measured the remained radioactivity after single pass of PBSCs. COMP-Ang1 priming increased the engraftment by about 1.5 folds compared to control(p<0.05). Finally, injection of COMP-Ang1 primed PBSCs resulted in superior perfusion ratio in nude mouse hindlimb ischemia at days 21 (perfusion ratio: 0.65±0.09 vs 0.27±0.12 in COMP-Ang1 primed group and vehicle-treated group, respectively, p<0.05). Conclusion : COMP-Ang1 priming was found to increase commitment to endothelial lineage and engraftment to ischemic tissue of PBSCs, which suggested a potential role of COMP-Ang1 as a priming agent potentiating stem cell therapy.
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