Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases
Liver tissue engineering at extrahepatic sites in mice as a potential new therapy for genetic liver diseases
复制标题
DOI：
10.1002/hep.20484
复制
发表时间：
2005-01-01
期刊：
影响因子：
13.5
通讯作者：
Kay, MA
中科院分区：
文献类型：
--
作者：
Ohashi, K;Waugh, JM;Kay, MA
已提出使用肝细胞移植的肝组织工程作为全器官移植或肝脏定向基因治疗的替代方案，以纠正各种类型的肝功能不全。当移植到同系小鼠的肾囊下时，肝细胞无法维持。然而，当我们将从Engelbreth-Holm-Swarm细胞中提取的细胞外基质成分移植到肝细胞时，肝细胞存活了至少140天，并形成了小肝组织。 A 型血友病小鼠的肝脏工程重建了 5% 至 10% 的正常凝血活性，足以减少出血时间并具有治疗效果。相反，皮下空间不支持 Engelbreth-Holm-Swarm 凝胶基质的肝细胞持续存活。我们假设在移植部位建立局部血管网络将减少移植物损失。为了测试这个想法，我们在肝细胞移植到皮下空间之前提供了一种有效的血管生成剂。通过此程序，在实验期间（120 天）实现了持续存活。为了确定这些工程化肝组织在体内也保留了其天然再生潜力，我们对幼稚肝脏诱导了两种不同模式的增殖刺激，并证实肝外组织内的肝细胞再生后具有与幼稚肝脏相似的活性。总之，我们的研究表明，肝组织可以在肝外部位进行改造和维护，保留其体内再生能力，并用于成功治疗遗传性疾病。
Liver tissue engineering using hepatocyte transplantation has been proposed as an alternative to whole-organ transplantation or liver-directed gene therapy to correct various types of hepatic insufficiency. Hepatocytes are not sustained when transplanted under the kidney capsule of syngeneic mice. However, when we transplanted hepatocytes with the extracellular matrix components extracted from Engelbreth-Holm-Swarm cells, hepatocytes survived for at least 140 days and formed small liver tissues. Liver engineering in hemophilia A mice reconstituted 5% to 10% of normal clotting activity, enough to reduce the bleeding time and have a therapeutic benefit. Conversely, the subcutaneous space did not support the persistent survival of hepatocytes with Engelbreth-Holm-Swarm gel matrix. We hypothesized that establishing a local vascular network at the transplantation site would reduce graft loss. To test this idea, we provided a potent angiogenic agent before hepatocyte transplantation into the subcutaneous space. With this procedure, persistent survival was achieved for the length of the experiment (120 days). To establish that these engineered liver tissues also retained their native regeneration potential in vivo, we induced two different modes of proliferative stimulus to the naive liver and confirmed that hepatocytes within the extrahepatic tissues regenerated with activity similar to that of naive liver. In conclusion, our studies indicate that liver tissues can be engineered and maintained at extrahepatic sites, retain their capacity for regeneration in vivo, and used to successfully treat genetic disorders.