Local injection of stem cell factor (SCF) improves myocardial homing of systemically delivered c-kit plus bone marrow-derived stem cells
Local injection of stem cell factor (SCF) improves myocardial homing of systemically delivered c-kit plus bone marrow-derived stem cells
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DOI：
10.1093/cvr/cvm027
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发表时间：
2008-01-01
影响因子：
10.8
通讯作者：
Frey, Norbert
中科院分区：
文献类型：
--
作者：
Lutz, Matthias;Rosenberg, Mark;Frey, Norbert
目的最近的研究表明，干细胞治疗可能会减轻心肌梗死的不利影响。然而，这些报告中的大多数仅观察到对心脏功能的适度影响，这表明在广泛临床使用之前仍需要改进。一种潜在的方法是增加干细胞向心脏的迁移。因此，我们测试了局部给予干细胞因子（SCF）是否可以改善心肌梗死后静脉输注lin-/c-kit+干细胞的心肌归巢。方法和结果通过结扎左前降支动脉诱导小鼠心肌梗死，并将2.5 μ g干细胞因子注射到心肌梗死周围区域。假手术小鼠和心肌内注射磷酸盐缓冲盐水（PBS）的动物作为对照。心肌梗死后24小时，通过磁性细胞分选从小鼠骨髓中分离lin-/c-kit+干细胞，用绿色荧光细胞追踪剂CFDA或（111）铟标记，随后通过尾静脉全身输注750 000个标记细胞。分别在另外24或72小时后（即心肌梗死后48和96小时），取出心脏并分析干细胞的心肌归巢。绿色荧光干细胞仅在先前接受SCF治疗的动物的梗塞周围区域中检测到。放射性测量显示，与注射PBS的动物相比，心肌内注射SCF显著增强了lin-/c-kit+干细胞的心肌归巢（3.58 +/- 0.53 vs. 2.28 +/- 0.23 cpm/mg/10（6）cpm，+60%，P < 0.05）和无心肌梗死的假手术小鼠（3.58 ± 0.53 vs. 1.95 +/- 0.22 cpm/mg/10（6）cpm，+85%，P < 0.01）。干细胞注射后72 h获得了类似的结果。结论我们证明了SCF的心肌内给药可持续地将更多的lin-/c-kit+干细胞导向心脏。未来的研究将显示更高水平的心肌SCF（即通过病毒介导的基因转移）是否可以进一步改善全身递送的c-kit+干细胞的归巢，从而有利地影响心肌梗死后的心脏重塑。
Aims Recent studies have shown that stem cell therapy may alleviate the detrimental effects of myocardial infarction. Yet, most of these reports observed only modest effects on cardiac function, suggesting that there still is need for improvement before widespread clinical use. One potential approach would be to increase migration of stem cells to the heart. We therefore tested whether local administration of stem cell factor (SCF) improves myocardial homing of intravenously infused lin-/c-kit+ stem cells after myocardial infarction.Methods and results Myocardial infarction was induced in mice via ligation of the left anterior descending artery and 2.5 mu g of SCF were injected into the peri-infarct zone. Sham-operated mice and animals with intramyocardial injection of phosphate-buffered saline (PBS) served as controls. Twenty-four hours after myocardial infarction, lin-/c-kit+ stem cells were separated from murine bone marrow by magnetic cell sorting, labelled with the green fluorescent cell tracker CFDA or (111)Indium, and subsequently 750 000 labelled cells were systemically infused via the tail vein. Another 24 or 72 h later, respectively (i.e. 48 and 96 h after myocardial infarction), hearts were removed and analysed for myocardial homing of stem cells. Green fluorescent stem cells were exclusively detected in the peri-infarct zone of animals having prior SCF treatment. Radioactive measurements revealed that an intramyocardial SCF injection significantly amplified myocardial homing of lin-/c-kit+ stem cells compared to animals with PBS injections (3.58 +/- 0.53 vs. 2.28 +/- 0.23 cpm/mg/10(6)cpm, +60%, P < 0.05) and sham-operated mice without myocardial infarction (3.58 0.53 vs. 1.95 +/- 0.22 cpm/mg/10(6)cpm, +85%, P < 0.01). Similar results were obtained 72 h after stem cell injection.Conclusion We demonstrate that intramyocardial administration of SCF sustainably directs more lin-/c-kit+ stem cells to the heart. Future studies will have to show whether higher levels of myocardial SCF (i.e. by virus-mediated gene transfer) can further improve homing of systemically delivered c-kit+ stem cells and thus favourably influence cardiac remodelling following myocardial infarction.