Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium.
Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium.
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DOI：
10.1161/circresaha.109.196030
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发表时间：
2010-06-11
影响因子：
20.1
通讯作者：
Dzau VJ
中科院分区：
文献类型：
--
作者：
Huang J;Zhang Z;Guo J;Ni A;Deb A;Zhang L;Mirotsou M;Pratt RE;Dzau VJ
虽然间充质干细胞（MSC）移植已被证明可以促进体内急性心肌损伤的心脏修复，但其整体恢复能力似乎受到限制，主要是由于缺血心肌中细胞活力差和植入率低。特定的趋化因子在梗死心肌中上调。然而，MSC中相应的趋化因子受体（例如CCR 1、CXCR 2）的表达水平非常低。我们假设这种不一致性可能是MSC植入和存活率差的原因。确定在MSC中CCR 1或CXCR 2趋化因子受体的过表达是否增加了它们在梗死心肌中注射后的细胞存活、迁移和植入。CCR 1的过表达，而不是CXCR 2，显着增加趋化因子诱导的小鼠MSC迁移，并保护MSC在体外凋亡。此外，当在冠状动脉结扎后1小时心肌内注射MSC时，CCR 1-MSC在心肌梗死（MI）后3天以显著高于对照-MSC或CXCR 2-MSC的水平在梗死心肌中积累。注射CCR 1-MSC的心脏在MI后三天表现出梗死面积的显著减小、心肌细胞凋亡的减少和损伤心肌中毛细血管密度的增加。此外，心肌内注射CCR 1-MSCs可预防心肌梗死后4周的心脏重塑并恢复心脏功能。我们的研究结果表明，在体外和体内有益的影响，干细胞的遗传修饰。趋化因子受体的过表达促进了MSCs的迁移、存活和植入，为心肌损伤的治疗提供了新的思路。
Although mesenchymal stem cell (MSC) transplantation has been shown to promote cardiac repair in acute myocardial injury in vivo, its overall restorative capacity appears to be restricted mainly due to poor cell viability and low engraftment in the ischemic myocardium. Specific chemokines are upregulated in the infarcted myocardium. However the expression levels of the corresponding chemokine receptors (e.g. CCR1, CXCR2) in MSCs are very low. We hypothesized that this discordance may account for the poor MSC engraftment and survival. To determine whether overexpression of CCR1 or CXCR2 chemokine receptors in MSCs augments their cell survival, migration and engraftment after injection in the infarcted myocardium. Overexpression of CCR1, but not CXCR2, dramatically increased chemokine-induced murine MSC migration and protected MSC from apoptosis in vitro. Moreover, when MSCs were injected intramyocardially one hour after coronary artery ligation, CCR1-MSCs accumulated in the infarcted myocardium at significantly higher levels than control-MSCs or CXCR2-MSCs three days post-myocardial infarction (MI). CCR1-MSC injected hearts exhibited a significant reduction in infarct size, reduced cardiomyocytes apoptosis and increased capillary density in injured myocardium three days post-MI. Furthermore, intramyocardial injection of CCR1-MSCs prevented cardiac remodeling and restored cardiac function 4 weeks post-MI. Our results demonstrate the in vitro and in vivo salutary effects of genetic modification of stem cells. Specifically, overexpression of chemokine receptor enhances the migration, survival and engraftment of MSCs, and may provide a new therapeutic strategy for the injured myocardium.