Transplantation of embryonic stem cell-derived endodermal cells into mice with induced lethal liver damage
Transplantation of embryonic stem cell-derived endodermal cells into mice with induced lethal liver damage
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DOI：
10.1634/stemcells.2007-0199
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发表时间：
2007-01-01
期刊：
影响因子：
5.2
通讯作者：
Ikai, Iwao
中科院分区：
文献类型：
--
作者：
Ishii, Takamichi;Yasuchika, Kentaro;Ikai, Iwao
胚胎干细胞是细胞治疗的潜在细胞来源。然而，没有证据表明使用干细胞来源的肝细胞进行细胞移植在治疗上是有效的。本研究的主要目的是评估干细胞来源的内皮细胞移植到肝损伤模型中的治疗效果。β-半乳糖苷酶标记的小鼠胚胎干细胞被分化为产生甲胎蛋白(AFP)的内皮细胞。在白蛋白增强子/启动子的控制下，AFP产生细胞或ESCs被移植到表达白喉毒素(DT)受体的转基因小鼠中。DT对受体肝细胞有选择性损伤作用。尽管细胞移植后7天，移植的甲胎蛋白产生细胞只重新填充了总肝脏质量的3.4%，但到第35天，它们取代了32.8%的肝脏。然而，停止给药后，移植细胞减少(第40天18.3%，第50天7.9%)，到第60-90天观察到很少的供体细胞。AFP细胞移植组的存活率(66.7%)明显高于假手术组(17.6%)。在AFP产生细胞移植组中，到第50天时没有发现肿瘤；然而，在移植后60天或更长时间内，脾畸胎瘤形成。胚胎干细胞移植对小鼠的存活率没有影响，而且移植后35天胚胎干细胞移植组肿瘤发生率较高。总之，这项研究首次证明，胚胎干细胞来源的内皮细胞提高了移植到诱发肝细胞损伤的小鼠的存活率。
ESCs are a potential cell source for cell therapy. However, there is no evidence that cell transplantation using ESC-derived hepatocytes is therapeutically effective. The main objective of this study was to assess the therapeutic efficacy of the transplantation of ESC-derived endodermal cells into a liver injury model. The beta-galactosidase-labeled mouse ESCs were differentiated into alpha-fetoprotein (AFP)-producing endodermal cells. AFP-producing cells or ESCs were transplanted into transgenic mice that expressed diphtheria toxin (DT) receptors under the control of an albumin enhancer/ promoter. Selective damage was induced in the recipient hepatocytes by the administration of DT. Although the transplanted AFP-producing cells had repopulated only 3.4% of the total liver mass 7 days after cell transplantation, they replaced 32.8% of the liver by day 35. However, these engrafted cells decreased (18.3% at day 40 and 7.9% at day 50) after the cessation of DT administration, and few donor cells were observed by days 60-90. The survival rate of the AFP-producing cell-transplanted group (66.7%) was significantly higher in comparison with that of the sham-operated group (17.6%). No tumors were detected by day 50 in the AFP-producing cell-transplanted group; however, splenic teratomas did form 60 days or more after transplantation. ESC transplantation had no effect on survival rates; furthermore, there was a high frequency of tumors in the ESC-transplanted group 35 days after transplantation. In conclusion, this study demonstrates, for the first time, that ESC-derived endodermal cells improve the survival rates after transplantation into mice with induced hepatocellular injury.