Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
J Cardiovasc Pharmacol. 2010 May;55(5):496-505. doi: 10.1097/FJC.0b013e3181d7a384.
Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are crucial for homing and migration of multiple stem cell types. Their potential role in mediating bone marrow-derived mesenchymal stem cell (BMSC) migration in areas of myocardial infarction (MI) has not been demonstrated. In this study, rat heart MI was created by left coronary artery ligation, and green fluorescent protein-labeled BMSCs were directly infused into the left ventricular cavity. Reverse transcriptase-polymerase chain reaction and Western blot analysis showed that SDF-1 was predominantly localized in the MI lesion, and its levels peaked by 3 to 7 days and were maintained at least 14 days. Additionally, this was matched with increased accumulation of BMSCs and an improvement in cardiac function. Furthermore, this effect was blocked by the phosphoinositide 3-kinase inhibitor, LY294002. In vitro experiments showed that CXCR4 expression by BMSCs was elevated during hypoxia and SDF-1 induced a concentration-dependent migration of BMSCs. This migration was CXCR4-dependent as confirmed by its total inhibition by AMD3100, a CXCR4-specific antagonist. Migration was also almost completely blocked by LY294002. Analysis showed that phosphorylated Akt was highly increased in SDF-1-treated BMSCs. Together these results demonstrated that SDF-1/CXCR4 may mediate the migration of BMSCs toward heart MI through activation of PI3K/Akt.
基质细胞衍生因子-1（SDF-1）及其受体 CXCR4 对于多种干细胞的归巢和迁移至关重要。它们在介导骨髓间充质干细胞（BMSC）向心肌梗死（MI）区域迁移中的潜在作用尚未得到证实。在这项研究中，通过左冠状动脉结扎创建大鼠心脏 MI，并将绿色荧光蛋白标记的 BMSC 直接注入左心室腔。逆转录-聚合酶链反应和 Western blot 分析显示，SDF-1 主要定位于 MI 病变部位，其水平在 3 至 7 天达到峰值，并至少维持 14 天。此外，这与 BMSC 的积累增加和心脏功能的改善相匹配。此外，这种作用被磷酸肌醇 3-激酶抑制剂 LY294002 阻断。体外实验表明，BMSC 中的 CXCR4 表达在缺氧和 SDF-1 诱导下升高，BMSC 呈浓度依赖性迁移。这种迁移是由 CXCR4 依赖性的，因为其特异性拮抗剂 AMD3100 可完全阻断。LY294002 也几乎完全阻断迁移。分析表明，SDF-1 处理的 BMSC 中磷酸化 Akt 显著增加。这些结果表明，SDF-1/CXCR4 可能通过激活 PI3K/Akt 介导 BMSC 向 MI 的迁移。
