Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Drug Metab Dispos. 2010 Jun;38(6):988-94. doi: 10.1124/dmd.109.031831. Epub 2010 Mar 12.
HepaRG cells, derived from a female hepatocarcinoma patient, are capable of differentiating into biliary epithelial cells and hepatocytes. More importantly, differentiated HepaRG cells are able to maintain activities of many xenobiotic-metabolizing enzymes, and expression of the metabolizing enzyme genes can be induced by xenobiotics. The ability of these cells to express and induce xenobiotic-metabolizing enzymes is in stark contrast to the frequently used HepG2 cells. The previous studies have mainly focused on a set of selected genes; therefore, it is of significant interest to know the extent of similarity of gene expression at whole genome levels in HepaRG cells and HepG2 cells compared with primary human hepatocytes and human liver tissues. To accomplish this objective, we used Affymetrix (Santa Clara, CA) U133 Plus 2.0 arrays to characterize the whole genome gene expression profiles in triplicate biological samples from HepG2 cells, HepaRG cells (undifferentiated and differentiated cells), freshly isolated primary human hepatocytes, and frozen liver tissues. After using similarity matrix, principal components, and hierarchical clustering methods, we found that HepaRG cells globally transcribe genes at levels more similar to human primary hepatocytes and human liver tissues than HepG2 cells. In particular, many genes encoding drug-processing proteins are transcribed at a more similar level in HepaRG cells than in HepG2 cells compared with primary human hepatocytes and liver samples. The transcriptomic similarity of HepaRG with primary human hepatocytes is encouraging for use of HepaRG cells in the study of xenobiotic metabolism, hepatotoxicology, and hepatocyte differentiation.
HepaRG 细胞源自一位女性肝癌患者，能够分化为胆管上皮细胞和肝细胞。更重要的是，分化的 HepaRG 细胞能够保持许多外源物质代谢酶的活性，并且外源物质能够诱导这些代谢酶基因的表达。这些细胞表达和诱导外源物质代谢酶的能力与常用的 HepG2 细胞形成鲜明对比。以前的研究主要集中在一组选定的基因上；因此，了解 HepaRG 细胞和 HepG2 细胞与原代人肝细胞和人肝组织在全基因组水平上的基因表达相似程度具有重要意义。为了实现这一目标，我们使用 Affymetrix（加利福尼亚州圣克拉拉）U133 Plus 2.0 阵列来描述 HepG2 细胞、HepaRG 细胞（未分化和分化细胞）、新鲜分离的原代人肝细胞和冷冻肝组织的三重生物学样本的全基因组基因表达谱。在使用相似性矩阵、主成分和层次聚类方法后，我们发现 HepaRG 细胞在转录水平上与原代人肝细胞和人肝组织更为相似，而不是 HepG2 细胞。特别是，许多编码药物处理蛋白的基因在 HepaRG 细胞中的转录水平与 HepG2 细胞相比，与原代人肝细胞和肝样本更为相似。HepaRG 与原代人肝细胞的转录组相似性令人鼓舞，可将 HepaRG 细胞用于外源物质代谢、肝毒性和肝细胞分化的研究。
