肝脏微环境中IGF-2在移植细胞再殖肝脏的作用及其机制研究

作为原位肝移植的替代方案，细胞移植在终末期肝病治疗中具有重要的应用前景。而移植细胞在宿主肝脏内增殖缓慢以及动物模型中实现肝脏再殖的调控机制还缺乏认识，极大地限制了其临床应用。现有的研究还未提出具有临床转化的促增殖方案以及如何解决老年患者衰老肝细胞增殖抑制问题。前期研究中，申请人证明了年轻肝脏微环境可以使得衰老肝细胞恢复增殖能力，并发现宿主微环境中存在着潜在促进细胞增殖的胰岛素样生长因子IGF-2，也证明了IGF-2与移植细胞的增殖速率和再殖效率成正相关。因此申请人提出“年轻微环境中IGF-2促进并逆转衰老供体细胞增殖能力，实现衰老逆转”的设想。本课题拟采用可实现肝脏再殖的FAH-/-小鼠模型，探讨IGF-2促进移植细胞再殖肝脏并逆转细胞衰老的作用及调控机制。通过建立基于IGF-2的干预手段，力争找到可以破解限制肝脏疾病细胞治疗向临床过度的瓶颈因素并为基于衰老的增殖相关疾病治疗提供理论基础。

At present cell transplantation, instead of orthotopic liver transplantation, is a promising option for cellular therapy of end-stage liver diseases. However, the inability to efficiently expand transplanted cells in recipient liver is one of the main bottlenecks of therapeutic liver repopulation. And the underlying molecular mechanisms of cell repopulation need to be better defined in order to translate this technique into clinical use. Creation of a suitable hepatic microenvironment that can stimulate proliferation in transplanted cells or senescent hepatocytes still remain elusive and are not well defined. Our early work has been concluded that proliferation of senescent hepatocytes is reversed after transplanted into young microenvironment. And we also found that insulin-like growth factor 2 (IGF-2) was up-regulated in young hepatic microenvironment of FAH-/- mice and secreted by the host hepatocytes. When down-regulation the expression of IGF-2, the repopulated rate of transplanted hepatocytes was decreased. In addition, we identified IGF-2 declined in aged environment when compared with young mice, followed with weak repopulation. All of these results indicated a hypothesis that IGF-2 could promote liver repopulation of cell transplantation and reverse proliferated ability of senescent hepatocytes. In this project, based on Fumarylacetoacetate hydrolase knockout (Fah-/-) mouse that is an excellent repopulation model, we will carry out hepatocytes transplantation to confirm the valid effect and the mechanism of IGF-2 on increased proliferation of transplanted hepatocytes or senescent hepatocytes. Then we try to create the optimal dosage, route, and interval of administration of IGF-2 by intraperitoneal (i.p.) injection, which are more suitable for clinical use. Our aim is to further characterize IGF-2 is one of the possible driving forces for the growth of transplanted cells and understanding the mechanisms regulating repopulation can improve the effect of transplantation, which is very important in clinic in the future, and offer a possible technological strategy to achieve therapeutic repopulation.