背景:间充质干细胞/基质细胞(MSC)已用于各种疾病的临床试验。这些具有某些显着的功能,例如归巢到炎症部位,组织修复,和免疫调节。在许多临床前研究中,给予外周静脉的MSC表现出有效的治疗结果。然而,大多数静脉内给药的MSCs被截留在肺中,归巢到目标地点不到1%。这主要是因为MSCs与肺中的血管内皮细胞粘附。为了防止这种粘连,我们使用抗生物素蛋白-生物素复合物(ABC)方法,用聚乙二醇(PEG;一种生物相容性聚合物)修饰MSCs的表面.
方法:使用ABC法用PEG修饰MSC的表面。然后,评估了细胞对小鼠主动脉内皮细胞的粘附和PEG修饰的MSCs的组织分布。此外,使用四氯化碳诱导的急性肝衰竭模型小鼠评估PEG修饰的MSCs对受损肝脏的归巢和治疗效果。
结果:在小鼠静脉注射后,PEG修饰显着抑制了MSCs对培养的小鼠主动脉内皮细胞的粘附以及MSCs在肺中的截留。PEG修饰的MSCs有效地归巢于四氯化碳诱导的急性肝衰竭模型小鼠的损伤肝脏。更重要的是,细胞显着抑制血清转氨酶水平和白细胞浸润到受损的肝脏。
结论:这些结果表明,对MSCs表面的PEG修饰可以抑制静脉内施用的MSCs的肺截留,并改善其归巢至受损肝脏。
Mesenchymal stem/stromal cells (MSCs) have been used in clinical trials for various diseases. These have certain notable functions such as homing to inflammation sites, tissue repair, and immune regulation. In many pre-clinical studies, MSCs administered into peripheral veins demonstrated effective therapeutic outcomes. However, most of the intravenously administered MSCs were entrapped in the lung, and homing to target sites was less than 1%. This occurred mainly because of the adhesion of MSCs to vascular endothelial cells in the lung. To prevent this adhesion, we modified the surface of MSCs with polyethylene glycol (PEG; a biocompatible polymer) using the avidin-biotin complex (ABC) method.
The surface of MSCs was modified with PEG using the ABC method. Then, the cell adhesion to mouse aortic endothelial cells and the tissue distribution of PEG-modified MSCs were evaluated. Moreover, the homing to the injured liver and therapeutic effect of PEG-modified MSCs were evaluated using carbon tetrachloride-induced acute liver failure model mice.
The PEG modification significantly suppressed the adhesion of MSCs to cultured mouse aortic endothelial cells as well as the entrapment of MSCs in the lungs after intravenous injection in mice. PEG-modified MSCs efficiently homed to the injured liver of carbon tetrachloride-induced acute liver failure model mice. More importantly, the cells significantly suppressed serum transaminase levels and leukocyte infiltration into the injured liver.
These results indicate that PEG modification to the surface of MSCs can suppress the lung entrapment of intravenously administered MSCs and improve their homing to the injured liver.