Comparative Study of Transplantation of Hepatocytes at Various Differentiation Stages Into Mice With Lethal Liver Damage
Comparative Study of Transplantation of Hepatocytes at Various Differentiation Stages Into Mice With Lethal Liver Damage
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DOI：
10.3727/096368912x636957
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发表时间：
2012-01-01
影响因子：
3.3
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
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作者：
Kamimura, Ryo;Ishii, Takamichi;Uemoto, Shinji
利用诱导多能干细胞（iPSC）或胚胎干细胞（ESC）的肝细胞移植已被预期提供肝移植的替代方案。然而，仍然不确定哪种细胞类型最适合细胞移植。特别是，目前尚不清楚是否有足够的肝功能的成熟肝细胞或具有较高增殖能力的未成熟肝祖细胞将提供更好的结果。本研究的主要目的是探讨不同分化阶段肝细胞移植的治疗效果。我们利用了在白蛋白增强子/启动子控制下表达白喉毒素（DT）受体的转基因小鼠。将ESC衍生的内胚层细胞、胎肝细胞和成体肝细胞移植到这些实验诱导的DT给药引起的致死性急性肝损伤小鼠中。用增强型绿色荧光蛋白标记移植细胞。我们评估了它们对生存的影响。在移植后35天，与假手术组（2/25，8%）、胎儿肝细胞移植组（1/20，5%）和ESC来源的内胚层细胞移植组（0/21，0%）相比，成人肝细胞移植组的存活率（8/20，40%）显著提高。成年肝细胞在受体肝脏中增殖，并取代了大部分肝实质。与移植未成熟细胞相比，移植成人肝细胞治疗急性肝衰竭显著提高了存活率，因此表明在细胞移植治疗急性肝衰竭之前，ESC和iPSC应分化为成熟肝细胞。
Hepatocyte transplantation utilizing induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs) has been expected to provide an alternative to liver transplantation. However, it remains uncertain precisely which cell type is the best suited for cell transplantation. In particular, it is unclear whether mature hepatocytes, which have sufficient liver function, or immature hepatic progenitor cells, which have a higher proliferative capacity, will provide a better outcome. The main objective of this study was to investigate the therapeutic efficacy of the transplantation of hepatocytes at various differentiation stages. We utilized transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/promoter. ESC-derived endodermal cells, fetal hepatocytes, and adult hepatocytes were transplanted into these mice with experimentally induced lethal acute liver injury caused by DT administration. The transplanted cells were marked by enhanced green fluorescent protein. We evaluated their effects on survival. At 35 days after transplantation, the survival rate of the adult hepatocyte-transplanted group (8/20, 40%) was significantly improved in comparison to that of the sham-operated group (2/25, 8%), the fetal hepatocyte-transplanted group (1/20, 5%), and the ESC-derived endodermal cell-transplanted group (0/21, 0%). The adult hepatocytes proliferated in the recipient livers and replaced a large part of their parenchyma. The transplantation of adult hepatocytes for acute liver failure significantly improved the survival rate in comparison to that of transplantation of immature cells, thus suggesting that ESCs and iPSCs should be differentiated into mature hepatocytes before cell transplantation for acute liver failure.