Department of Cell Biology, Center for Stem Cell and Medicine, Second Military Medical University, Shanghai, 200433, China.
Translational Medical Center for Stem Cell Therapy & Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China.
Cell Death Dis. 2018 Jan 18;9(2):26. doi: 10.1038/s41419-017-0186-1.
Hepatocyte transplantation holds great promise as an alternative to orthotopic organ transplantation in the treatment of liver diseases. However, obtaining clinically meaningful levels of liver repopulation has not been achieved because the mechanisms regulating hepatocyte proliferation in recipient livers have not yet been well characterized. In the mouse model of Hereditary Tyrosinemia Type I, the fumarylacetoacetate hydrolase-deficient (Fah) mouse, we found gradually increasing expression level of insulin-like growth factor 2 (IGF2) in the hepatocytes of host livers. Similarly, high levels of IGF2 were found in the livers of patients with deficient FAH activity. Recombinant IGF2 directly promotes proliferation of primary hepatocytes in vitro. Inhibition on IGF2 expression through the interruption of PI3K/Akt and MAPK pathways significantly reduced the level of liver repopulation in Fah mice. Interestingly, treatment with IGF2 before hepatocyte transplantation generally improved the amount of liver repopulation seen in various mice models of liver injury. Altogether, these findings underscore the underlying mechanisms of therapeutic liver repopulation in Fah mice, and indicate that IGF2 is a potential hepatocyte mitogen for liver cell transplantation therapies.
肝细胞移植作为治疗肝脏疾病的原位器官移植的替代方法具有广阔的前景。然而，由于尚未很好地阐明调节受体肝脏中肝细胞增殖的机制，因此尚未获得具有临床意义的肝再殖水平。在遗传性酪氨酸血症 I 型的小鼠模型中，我们发现缺乏琥珀酸酰乙酰乙酸水解酶（Fah）的小鼠的肝细胞中胰岛素样生长因子 2（IGF2）的表达水平逐渐增加。同样，在 FAH 活性缺乏的患者的肝脏中也发现了高水平的 IGF2。重组 IGF2 可直接促进原代肝细胞在体外增殖。通过中断 PI3K/Akt 和 MAPK 途径抑制 IGF2 的表达可显著降低 Fah 小鼠的肝再殖水平。有趣的是，在肝细胞移植前用 IGF2 治疗通常可以改善各种肝损伤小鼠模型中观察到的肝再殖量。总之，这些发现强调了 Fah 小鼠治疗性肝再殖的潜在机制，并表明 IGF2 是肝细胞移植治疗的潜在肝细胞有丝分裂原。
