The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain.
The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain.
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DOI：
10.1161/strokeaha.110.606368
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发表时间：
2011-10
期刊：
影响因子：
8.3
通讯作者：
Guzman R
中科院分区：
文献类型：
--
作者：
Andres RH;Choi R;Pendharkar AV;Gaeta X;Wang N;Nathan JK;Chua JY;Lee SW;Palmer TD;Steinberg GK;Guzman R
炎症反应是缺血性中风的关键组成部分。除了其生理作用外，免疫细胞跨内皮募集背后的机制也为转化干细胞疗法提供了独特的治疗机会。最近的报告表明，神经干细胞（NSC）在血管内输送后归巢到受伤的大脑区域。然而，跨内皮募集过程的潜在机制仍然很大程度上未知。在这里，我们描述了趋化因子 CCL2 及其受体 CCR2 在缺血后 NSC 靶向归巢中的关键作用。使用小鼠缺氧缺血模型诱导中风后 24 小时，将 CCR2+/+ 和 CCR2−/− 报告 NSC 进行动脉内递送。使用组织学和生物发光成像来研究 NSC 归巢到缺血大脑。通过水平阶梯测试评估功能结果。使用从 CCR2+/+ 和 CCR2−/− 小鼠中分离的 NSC，我们发现受体缺陷显着损害跨内皮细胞渗出，特别是对 CCL2 的反应。因此，注射到 CCL2−/− 小鼠中的野生型 NSC 表现出显着降低的归巢能力。生物发光成像显示，与 CCR2−/− 细胞相比，移植后 6 小时内 CCR2+/+ 细胞大量募集。与移植 CCR2−/− NSC 的动物相比，在缺血性损伤后接受 CCR2+/+ 移植物的小鼠表现出神经功能缺损的恢复显着改善。 CCL2/CCR2 相互作用对于血管内递送的 NSC 响应缺血性损伤的跨内皮募集至关重要。这一发现可能对推进再生医学的微创血管内治疗或中枢神经系统疾病的细胞药物输送系统具有重大意义。
The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia. Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2−/− reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test. Using NSC isolated from CCR2+/+ and CCR2−/− mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2−/− mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2−/− cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2−/− NSC. The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.