IGF-2通过β-catenin促进肝再生的机制研究

Acute and chronic liver injury can both promote liver regeneration. The mechanism of liver regeneration after chronic liver injury has not yet been fully elucidated. Our previous study first time found that IGF-2 is overexpressed and promotes hepatocyte proliferation in a mouse model of chronic liver injury, and that IGF-2 is concentrated in the area surrounding the central venous area of the liver (CV area), which is also found in human chronic liver injury specimens obtained preliminary verification. However, the mechanism by which IGF-2 promotes liver regeneration is not clear. In addition, the regeneration of hepatocytes in different groups was significantly different. The proliferation of the CV area, especially Axin2-positive hepatocytes, was closely related to the Wnt / β-catenin signaling pathway. Based on this, we hypothesized that in chronic liver injury, IGF-2 promotes the regeneration of liver by promoting the proliferation of Axin2-positive hepatocytes in the CV area through β-catenin. This project intends to pass the clinical spectrum of chronic liver injury disease, in vitro and in vivo experiments to verify the scientific hypothesis. The results of the project are expected to further improve the molecular mechanism of IGF-2 activation and regulation and promote liver regeneration, and provide a new scientific basis for the diagnosis and treatment of liver regeneration after clinical liver injury.

急慢性肝损伤均能促进肝再生。慢性肝损伤后肝再生的具体机制仍未完全阐明。我们既往研究首次发现，IGF-2在小鼠慢性肝损伤模型中高表达并促进肝细胞增殖, 而且IGF-2集中表达在肝中央静脉周围区（CV区），这在人慢性肝损伤标本中也得到初步验证。但是，IGF-2通过何种机制促进肝再生并不清楚。另外，不同群体的肝细胞的再生差异明显，CV区特别是Axin2阳性的肝细胞增殖与Wnt/β-catenin信号通路密切相关。据此我们提出推测：慢性肝损伤中，IGF-2通过β-catenin促进CV区Axin2阳性肝细胞增殖从而促进肝脏的再生。本项目拟通过临床慢性肝损伤疾病谱、体外与体内实验验证该科学假设。项目成果有望对IGF-2激活调控促进肝再生分子机制进一步完善，为临床肝损伤后肝再生的诊治提供新的科学依据。

急慢性肝损伤均能促进肝再生。慢性肝损伤后肝再生的具体机制仍未完全阐明。我们既往研究首次发现，IGF-2在小鼠慢性肝损伤模型中高表达并促进肝细胞增殖, 而且IGF-2 集中表达在肝中央静脉周围区(CV区)。我们制备了载有IGF-2的Fe（III）@ TA @ IGF-2 200（TA200）水凝胶（IGF-2）用于受损肝细胞的再生。 Fe（III）@TA微球充当载体以实现IGF-2的持续释放，从而促进肝细胞的再生。半乳糖基化的壳聚糖可以显着增强肝细胞的特异性功能。对于四氯化碳（CCl4）诱导的人肝星状细胞系LX2损伤，IFG-2水凝胶可显着提高LX2细胞的存活率。在水凝胶处理的LX2细胞中检测到HNF-4α和转铁蛋白的表达，表明肝脏的特异性功能也得以恢复。IGF-2水凝胶的力学性能、降解性能、生物相容性和缓释性能满足肝损伤修复的需要。这种水凝胶未来可用于促进肝脏再生和构建用于药物筛选的人工肝脏。