缺氧预处理的骨髓间充质干细胞在大鼠大面积肝切除模型中促进肝再生。
Hypoxia preconditioned bone marrow mesenchymal stem cells promote liver regeneration in a rat massive hepatectomy model.
作者信息
Yu Jun, Yin Shengyong, Zhang Wu, Gao Feng, Liu Yuanxing, Chen Zhiyun, Zhang Min, He Jiangjuan, Zheng Shusen
出版信息
Stem Cell Res Ther. 2013 Jul 15;4(4):83. doi: 10.1186/scrt234.
INTRODUCTION
Bone marrow mesenchymal stem cells (BMMSCs) have been reported to facilitate liver regeneration after toxic injuries. However, the effect of BMMSCs on liver regeneration after massive hepatectomy is barely studied. Here we explored whether infusion of BMMSCs promotes liver regeneration in a rat massive hepatectomy model.
METHODS
Hypoxia preconditioning was achieved by culturing BMMSCs under a hypoxia environment. Then 85% hepatectomy was performed and hypoxia or normoxia preconditioned BMMSCs were infused into the portal vein. A group of rats received vascular endothelial growth factor (VEGF) neutralizing antibody perioperatively, and underwent 85% hepatectomy and a subsequent infusion of hypoxia preconditioned BMMSCs to verify the role of VEGF in the effects of BMMSCs on liver regeneration. Liver samples were collected and liver regeneration was evaluated postoperatively.
RESULTS
Hypoxia preconditioning enhanced the expression of VEGF in BMMSCs in vitro. Infusion of BMMSCs promoted proliferation of hepatocytes, reflected by elevated cyclin D1 expression and proliferating cell nuclear antigen-positive hepatocytes. However, BMMSC infusion did not improve the serum albumin level, liver weight/body weight ratio, and survival after operation. Infusion of hypoxia preconditioned BMMSCs significantly elevated cyclin D1, proliferating cell nuclear antigen-positive hepatocytes, liver weight/body weight ratio, and survival compared with normoxia preconditioned BMMSCs, accompanied by an increased serum albumin level. The level of VEGF in liver homogenate was much higher in hypoxia preconditioned BMMSC-treated animals than in other groups. In addition, the perioperative injection of VEGF neutralizing antibody significantly blocked the therapeutic effects of hypoxia preconditioned BMMSCs on liver injury and regeneration in this model.
CONCLUSION
Hypoxia preconditioned BMMSCs enhanced liver regeneration after massive hepatectomy in rats, possibly by upregulating the level of VEGF.
引言
据报道，骨髓间充质干细胞（BMMSCs）有助于中毒性损伤后的肝脏再生。然而，BMMSCs对大规模肝切除术后肝脏再生的影响鲜有研究。在此，我们探讨了输注BMMSCs是否能促进大鼠大规模肝切除模型中的肝脏再生。
方法
通过在低氧环境下培养BMMSCs实现低氧预处理。然后进行85%肝切除术，并将低氧或常氧预处理的BMMSCs注入门静脉。一组大鼠在围手术期接受血管内皮生长因子（VEGF）中和抗体，并进行85%肝切除术及随后输注低氧预处理的BMMSCs，以验证VEGF在BMMSCs对肝脏再生作用中的角色。收集肝脏样本并在术后评估肝脏再生情况。
结果
低氧预处理增强了体外培养的BMMSCs中VEGF的表达。输注BMMSCs促进了肝细胞增殖，这通过细胞周期蛋白D1表达升高和增殖细胞核抗原阳性肝细胞得以体现。然而，输注BMMSCs并未改善血清白蛋白水平、肝重/体重比及术后生存率。与常氧预处理的BMMSCs相比，输注低氧预处理的BMMSCs显著提高了细胞周期蛋白D1、增殖细胞核抗原阳性肝细胞、肝重/体重比及生存率，同时血清白蛋白水平升高。低氧预处理的BMMSC治疗组动物肝脏匀浆中的VEGF水平远高于其他组。此外，围手术期注射VEGF中和抗体显著阻断了低氧预处理的BMMSCs对该模型中肝损伤和再生的治疗作用。
结论
低氧预处理的BMMSCs可能通过上调VEGF水平增强大鼠大规模肝切除术后的肝脏再生。
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