Department of Neurosurgery, Stanford Stroke Center, Stanford University, School of Medicine, 300 Pasteur Drive R211, Stanford, CA 94305-5327, USA.
Stroke. 2011 Oct;42(10):2923-31. doi: 10.1161/STROKEAHA.110.606368. Epub 2011 Aug 11.
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.
炎症反应是缺血性中风的一个关键组成部分。除了其生理作用外，免疫细胞跨内皮募集的机制也为转化干细胞治疗提供了独特的治疗机会。最近的报告表明，神经干细胞（NSC）在血管内给药后会归巢到受损的大脑区域。然而，跨内皮募集的过程中的机制在很大程度上仍然未知。在这里，我们描述趋化因子 CCL2 及其受体 CCR2 在缺血后 NSC 靶向归巢中的关键作用。
在小鼠缺氧缺血模型诱导中风 24 小时后，通过动脉内给予 CCR2+/+和 CCR2-/-报告 NSC。组织学和生物发光成像用于研究 NSC 归巢到缺血性大脑。使用水平梯测试评估功能结果。
使用从 CCR2+/+和 CCR2-/-小鼠分离的 NSC，我们表明受体缺陷显着损害了 CCL2 特异性的跨内皮细胞迁移。相应地，注射到 CCL2-/-小鼠中的野生型 NSC归巢显着减少。生物发光成像显示，与 CCR2-/-细胞相比，CCR2+/+细胞在移植后 6 小时内可大量募集。与移植 CCR2-/-NSC 的动物相比，接受 CCR2+/+移植物的缺血性损伤小鼠表现出明显改善的神经功能缺损恢复。
CCL2/CCR2 相互作用对于血管内给予的 NSC 对缺血性损伤的跨内皮募集至关重要。这一发现可能对推进微创性血管内治疗再生医学或基于细胞的药物输送系统治疗中枢神经系统疾病具有重要意义。
