Primary-like Human Hepatocytes Genetically Engineered to Obtain Proliferation Competence as a Capable Application for Energy Metabolism Experiments in In Vitro Oncologic Liver Models.
Primary-like Human Hepatocytes Genetically Engineered to Obtain Proliferation Competence as a Capable Application for Energy Metabolism Experiments in In Vitro Oncologic Liver Models.
复制标题
DOI：
10.3390/biology11081195
复制
发表时间：
2022-08-09
期刊：
影响因子：
4.2
通讯作者：
Damm, Georg
中科院分区：
文献类型：
--
作者：
Scheffschick, Andrea;Babel, Jonas;Sperling, Sebastian;Nerusch, Julia;Herzog, Natalie;Seehofer, Daniel;Damm, Georg
脂肪肝疾病是西方国家日益严重的健康问题。脂肪肝可导致肝细胞癌 (HCC)，这是一种由肝细胞（肝脏的主要细胞）产生的肝癌。脂肪肝如何发展成肝癌尚不清楚，也缺乏良好的细胞系统来研究这一问题。最近，已经产生了可以连续增殖的肝细胞，并建议用于肝细胞研究。在这项研究中，我们将这些不断增殖的人类肝细胞与正常人类肝细胞和肝癌细胞进行了比较，无论是否处于脂肪肝状态。我们发现这些增殖的肝细胞在能量代谢方面与肝癌细胞表现出许多相似之处，并得出结论，这些肝细胞可以作为肝癌研究的癌前模型，并且将成为肝癌研究的宝贵工具。非酒精性脂肪肝病（NAFLD）以肝脏中脂质堆积为特征，是西方国家肝脏疾病的最常见原因。 NAFLD 是发生肝细胞癌 (HCC) 的主要危险因素；然而，由于缺乏显示肝细胞增殖的肝脏模型，对肝癌发生的体外评估失败。 upcyte 肝细胞最初是为了克服原代人肝细胞 (PHH) 短缺而设计的，经过改造以获得持续增殖，因此可能成为 HCC 研究的合适工具。我们生成了 upcyte 肝细胞，称为 HepaFH3 细胞，并将其代谢特征与从切除肝脏中分离的 HepG2 肝癌细胞和 PHH 进行比较。为了显示 NAFLD 相关的 HCC，我们在所有肝脏模型中诱导脂肪变性。使用生化测定和蛋白质印迹分析来表征脂质积累、脂毒性和能量代谢。我们发现，增殖的 HepaFH3 细胞与 HepG2 相似，与 PHH 相比，两者都表现出更高的葡萄糖摄取率、乳酸水平和代谢率。汇合的 HepaFH3 细胞与 PHH 表现出一些相似之处，包括与增殖的 HepaFH3 细胞相比，转氨酶 AST 和 ALT 水平较高。我们建议将增殖的 HepaFH3 细胞作为 HCC 研究的癌前细胞模型，而汇合的 HepaFH3 细胞可以作为能量代谢研究的 PHH 替代物。
Fatty liver disease is an increasing health concern in Westernized countries. A fatty liver can lead to hepatocellular carcinoma (HCC), a type of liver cancer arising from hepatocytes, the major cells of the liver. How HCC may develop from the fatty liver is not known, and good cellular systems to investigate this are lacking. Recently, hepatocytes that can multiply continuously have been generated and suggested for hepatocyte research. In this study, we compared these continuously multiplying human hepatocytes to normal human hepatocytes and liver cancer cells, both within the state of fatty liver or not. We identified that these multiplying hepatocytes displayed many similarities to the liver cancer cells in terms of energy metabolism and concluded that these hepatocytes could be a pre-cancer model for liver cancer research and would be a valuable tool for HCC research. Non-alcoholic fatty liver disease (NAFLD), characterized by lipid accumulation in the liver, is the most common cause of liver diseases in Western countries. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC); however, in vitro evaluation of hepatic cancerogenesis fails due to a lack of liver models displaying a proliferation of hepatocytes. Originally designed to overcome primary human hepatocyte (PHH) shortages, upcyte hepatocytes were engineered to obtain continuous proliferation and, therefore, could be a suitable tool for HCC research. We generated upcyte hepatocytes, termed HepaFH3 cells, and compared their metabolic characteristics to HepG2 hepatoma cells and PHHs isolated from resected livers. For displaying NAFLD-related HCCs, we induced steatosis in all liver models. Lipid accumulation, lipotoxicity and energy metabolism were characterized using biochemical assays and Western blot analysis. We showed that proliferating HepaFH3 cells resemble HepG2, both showing a higher glucose uptake rate, lactate levels and metabolic rate compared to PHHs. Confluent HepaFH3 cells displayed some similarities to PHHs, including higher levels of the transaminases AST and ALT compared to proliferating HepaFH3 cells. We recommend proliferating HepaFH3 cells as a pre-malignant cellular model for HCC research, while confluent HepaFH3 cells could serve as PHH surrogates for energy metabolism studies.
登录
查看更多内容
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
5.5
作者：
Giulitti F;Petrungaro S;Mandatori S;Tomaipitinca L;de Franchis V;D'Amore A;Filippini A;Gaudio E;Ziparo E;Giampietri C
通讯作者：
Giampietri C
影响因子：
4.6
作者：
Garnier D;Li R;Delbos F;Fourrier A;Collet C;Guguen-Guillouzo C;Chesné C;Nguyen TH
通讯作者：
Nguyen TH
影响因子：
6.7
作者：
Lin，Huapeng;Wong，Grace L-H;Wong，Vincent W-S
通讯作者：
Wong，Vincent W-S
影响因子：
5.8
作者：
Farzaneh Z;Vosough M;Agarwal T;Farzaneh M
通讯作者：
Farzaneh M