Department of Cell Biology, Second Military Medical University, Shanghai, China.
Int J Biochem Cell Biol. 2012 Apr;44(4):648-58. doi: 10.1016/j.biocel.2012.01.002. Epub 2012 Jan 10.
Although embryonic stem (ES) cell-derived hepatocytes have the capacity for liver engraftment and repopulation, their in vivo hepatic function has not been analyzed yet. We aimed to determine the metabolic function and therapeutic action of ES cell-derived hepatocytes after serial liver repopulations in fumaryl acetoacetate hydrolase knockout (Fah(-/-)) mice. Albumin expressing (Alb(+)) cells were obtained by hepatic differentiation of ES cells using two frequently reported methods. After transplantation, variable levels of liver repopulation were found in Fah(-/-) mice recipients. FAH expressing (FAH(+)) hepatocytes were found either as single cells or as nodules with multiple hepatocytes. After serial transplantation, the proportion of the liver that was repopulated by the re-transplanted FAH(+) hepatocytes increased significantly. ES cell-derived FAH(+) hepatocytes were found in homogenous nodules and corrected the liver metabolic disorder of Fah(-/-) recipients and rescued them from death. ES cell-derived hepatocytes had normal karyotype, hepatocytic morphology and metabolic function both in vitro and in vivo. In conclusion, ES cell-derived hepatocytes were capable of liver repopulation and correction of metabolic defects after serial transplantation. Our results are an important piece of evidence to support future clinical applications of ES cell-derived hepatocytes in treating liver diseases.
虽然胚胎干细胞（ES）细胞衍生的肝细胞具有肝移植和再定植的能力，但它们的体内肝功能尚未得到分析。我们的目的是确定在 fumaryl acetoacetate hydrolase knockout (Fah(-/-)) 小鼠中进行连续肝再定植后，ES 细胞衍生的肝细胞的代谢功能和治疗作用。使用两种常用的方法，通过 ES 细胞的肝分化获得表达白蛋白的（Alb(+)) 细胞。移植后，在 Fah(-/-) 小鼠受体中发现了不同程度的肝再定植。FAH 表达（FAH(+)) 肝细胞作为单个细胞或具有多个肝细胞的结节存在。经过连续移植，由再移植的 FAH(+) 肝细胞重新定植的肝脏比例显著增加。在同质结节中发现 ES 细胞衍生的 FAH(+) 肝细胞，纠正了 fah(-/-) 受者的肝脏代谢紊乱，并使其免于死亡。ES 细胞衍生的肝细胞在体外和体内均具有正常的核型、肝细胞形态和代谢功能。总之，ES 细胞衍生的肝细胞能够在连续移植后进行肝再定植和纠正代谢缺陷。我们的研究结果为未来将 ES 细胞衍生的肝细胞应用于治疗肝脏疾病的临床应用提供了重要证据。
