Reprogramming induced pluripotent stem cells in the absence of c-Myc for differentiation into hepatocyte-like cells
Reprogramming induced pluripotent stem cells in the absence of c-Myc for differentiation into hepatocyte-like cells
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DOI：
10.1016/j.biomaterials.2011.05.009
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发表时间：
2011-09-01
期刊：
影响因子：
14
通讯作者：
Chiou, Shih-Hwa
中科院分区：
文献类型：
--
作者：
Li, Hsin-Yang;Chien, Yueh;Chiou, Shih-Hwa
具有四种重编程因子（Oct-4/Sox 2/Klf-4/c-Myc）的诱导多能干细胞（iPSC）已显示分化成肝谱系。然而，尚不清楚iPSC中c-Myc癌基因的消除是否影响肝分化或抑制体内肿瘤形成。在这项研究中，我们证明了没有c-Myc的iPSC有能力分化为具有生物学功能的肝细胞样细胞（iPSC-Heps）。如使用平面放射性核素成像和Hoechst标记测定所检测的，这些iPSC和iPSC-Heps倾向于在硫代乙酰胺（TAA）处理的小鼠中移动到损伤的肝脏区域。iPSC和iPSC-Heps但不是小鼠胚胎成纤维细胞（MEF）的静脉内移植减少了肝坏死面积，改善了肝功能，并将TAA治疗的小鼠从致命的急性肝功能衰竭（AHF）中拯救出来。此外，基于微阵列的生物信息学和定量RT-PCR显示，与MEFs相比，iPSC和iPSC-Hep中抗氧化基因的表达较高。NAC预处理的体内和体外研究证实，iPSC和iPSC-Hep可能抑制ROS产生并激活TAA损伤的肝脏中的抗氧化酶。在TAA处理的小鼠中移植后6个月，在非c-Myc iPSC移植物中未观察到肿瘤形成。因此，在无c-Myc的情况下重编程成体体细胞可以防止氧化应激诱导的损伤，并为AHF的肝再生提供更安全的替代方案。(C)2011爱思唯尔有限公司保留所有权利。
Induced pluripotent stem cells (iPSCs) with four reprogramming factors (Oct-4/Sox2/Klf-4/c-Myc) have been shown to differentiate into hepatic lineages. However, it was unclear whether obviation of the c-Myc oncogene in iPSCs affected hepatic differentiation or inhibited in vivo tumor formation. In this study, we demonstrated that iPSCs without c-Myc had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) with biological functions. As detected using planar-radionuclide imaging and Hoechst labeling assays, these iPSCs and iPSC-Heps tended to mobilize to the injured liver area in thioacetamide (TAA)-treated mice. Intravenous transplantation of both iPSCs and iPSC-Heps but not mouse embryonic fibroblasts (MEFs) reduced the hepatic necrotic area, improved liver functions, and rescued TAA-treated mice from lethal acute hepatic failure (AHF). In addition, microarray-based bioinformatics and quantitative RT-PCR showed high expression of antioxidant genes in iPSCs and iPSC-Heps compared to MEFs. In vivo and in vitro studies of NAC pretreatment confirmed that iPSCs and iPSC-Heps potentially suppressed ROS production and activated antioxidant enzymes in TAA-injured livers. Six months after transplantation in TAA-treated mice, tumor formation was not seen in non-c-Myc iPSC grafts. Therefore, reprogramming adult somatic cells without c-Myc may prevent oxidative stress-induced damage and provide a safer alternative for hepatic regeneration in AHF. (C) 2011 Elsevier Ltd. All rights reserved.